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The writer has done a thorough research even about the obscure and minor details related to the subject area. And also facts weren’t just dumped, but presented in an interesting manner.

As a whole, this book contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

Detoxification Of

The most important biochemical property of ROS is their reactivity with other biomolecules, which determines their half-life and the ability to diffuse away from the site of their production. The first and the only endothermic step in the reduction of molecular dioxygen leads to the formation of superoxide (O2'_) or hydroperoxyl (HO2'_) radicals. During its relatively short life (half-life 2 to 4 ms), O2' can oxidize amino acids like histidine, metionine, and tryptophan or reduce quinones and transition metal complexes of Fe3+ and Cu2+, thus affecting the activity of metal-containing enzymes 1 . Its protonated form, the hydroperoxyl radical, is predominant in acidic environment. It can cross biological membranes and subtract hydrogen atoms from polyunsaturated fatty acids, thus initiating lipid auto-oxidation. The second step leads to the formation of hydrogen peroxide (H2O2), a moderately active, relatively stable and therefore long-lived molecule with a half-life of 1 ms. Because of...

Detoxify The Phosphothioate By Phosphatase

Malathion, 2- (dimethoxyphosphinothioyl) thio butanedioic acid diethyl ester, is a water-insoluble phosphodithioate ester that has been used as an agricultural insecticide. Malathion is a poor inhibitor of cholinesterases. Its effectiveness as a safe insecticide is a result of the different rates at which humans and insects metabolize the chemical. Microsomal oxidation, which causes desulfuration, occurs slowly to form the phosphothioate (malaoxon), which is 10,000 times more active than the phosphodithioate (malathion) as a cholinesterase inhibitor. Insects detoxify the phosphothioate by a phosphatase, forming dimethyl phosphorothioate, which is inactive as an inhibitor. Humans, however, can rapidly hydrolyze malathion by a

Human Coppertransporting Atpases As Members Of The Ptype Atpase Family

In addition to their important role in delivering copper to the copper-dependent enzymes, human copper-transporting ATPases regulate the intracellular concentration of copper by removing excess copper from the cell. This detoxification function of copper-transporting ATPases is very similar to the functional role of bacterial Cd2+-ATPase and Pb2+-ATPases and likely appeared first during evolution. It was later extended to accommodate eucaryotic cell needs in having copper inside various cell organelles. To carry out this dual function, WNDP and MNKP have to be located, at least temporarily, in different cell compartments.

Artificial Cells Containing Bioadsorbents

For the removal of other uremic wastes need to be developed. The approach has also proved to be effective in removing toxic molecules in patients with severe liver failure, resulting in the recovery of consciousness of grade4 hepatic coma patients (Chang, 1972b, 1975g Gazzard etal., 1974). Detoxification is only one of the functions of the liver, and this approach is being used as the detoxification component of hybrid liver support systems that are being developed (Liu et al., 2001). The success in the clinical uses of artificial cells containing bioadsorbents for detoxification has led to an increasing interest in research and development in many other areas. One of these is in artificial cells containing immuoadsorbents (Chang, 1980d).

Other Data Relevant To An Evaluation Of Carcinogenicity And Its Mechanisms

Concise information is given on absorption, distribution (including placental transfer) and excretion in both humans and experimental animals. Kinetic factors that may affect the dose-response relationship, such as saturation of uptake, protein binding, metabolic activation, detoxification and DNA repair processes, are mentioned. Studies that indicate the metabolic fate of the agent in humans and in experimental animals are summarized briefly, and comparisons of data on humans and on animals are made when possible. Comparative information on the relationship between exposure and the dose that reaches the target site may be of particular importance for extrapolation between species. Data are given on acute and chronic toxic effects (other than cancer), such as

Application Of Computational Methods To Copper Proteins

In a recent work, a model for the incorporation of metal from the copper chaperone CCS into Cu,Zn SOD has been proposed (32). Previous studies have identified the human copper chaperone CCS as the presumed factor responsible for copper incorporation into SOD (34,35). The 3D structure of CCS was homology modeled using the periplasmic protein from the bacterial mercury-detoxification system (36) and the structure of one subunit of the human SOD dimeric enzyme (37) as templates. On the basis of the 3D model, a mechanism for the transfer of copper from CCS to SOD is proposed that accounts for electrostatic acceptor recognition, copper storage, and copper-transfer properties. The proposed model identifies a path for copper transfer based on the presence of differ

Nitrite Transport and Reduction

In plant cells, nitrite is the product ofnitrate reduction by NR. Plants can also acquire nitrite from the outside, by taking up either nitrite from the exogenous medium or gases from the atmosphere. In both cases it seems that nitrite never accumulates to high concentrations within the cell. Indeed, nitrite is highly toxic and its acid form, nitrous acid, is even more so (Sinclair, 1987). As discussed in Section II, nitrite is produced in the cytosol by cNR or at the plasma membrane by PM-NR. It must therefore be transported across the plastid membranes to be further reduced to ammonium by plastidic nitrite reductase (NiR, EC At the forefront of any discussion of the control of nitrite reduction must be recognition of the importance of the supply of reducing power, of which ammonium formation from nitrite requires considerable amounts. In this section, we present some recent data on the transport and reduction of nitrite, with a particular emphasis on alternative enzymatic...

Pharmacogenetic Mechanisms Of Human Drug Response

Mechanisms of variation of genetically altered human drug responses include the following (1) Modification of the absorption of the xenobiotic as could result from increased ''first pass metabolism by a rapid metabolizer enzyme, from decreased abundance of a transporter protein, or from enhanced excretion by the multidrug resistance receptor protein. Pharmacokinetic as well as pharmacodynamic mechanisms are represented by these examples. (2) Modification of the metabolism that results in modification of the rate or the pattern of elimination, detoxification, or activation of a given xenobiotic. If the main metabolic pathway leading to a harmless metabolite is blocked, the parent drug could accumulate and cause toxicity, or if the metabolism is shunted from the harmless to a toxic pathway, metabolites could cause toxic manifestations. An example of the first possibility is represented by the dramatic fall in blood pressure experienced by the poor metabolizer of debrisoquine after a...

Carbonyl Stress In Diabetes

The increase in lipoxidation and glycoxidation products in diabetes is the direct result of an increase in carbonyl precursors however, not all of these intermediates are derived from oxidative reactions. 3DG, for example, is formed nonoxidatively from Amadori compounds (34) or fructose-3-phos-phate (35) and is also increased in diabetes, along with increases in both pyrra-line and 3DG-arginine imidazolone (36) adducts that are derived from 3DG by nonoxidative mechanisms. MGO adducts to protein, including CEL and MOLD, are also increased in diabetes (37,38). Like 3DG, MGO is formed by anaerobic mechanisms, either enzymatically as an intermediate in amino acid catabolism or by (3-elimination reactions of triose phosphates (39,40). However, MGO may also be produced during the oxidative chemistry of both lipids and carbohydrates, so that its precise origin in vivo is unknown. In any case, the increase in 3DG, and possibly MGO, and their adducts to proteins suggests that limitations in...

Redox Biology and Life

In 1957, Denham Harman proposed the free radical theory of aging.6 His hypothesis suggested that consequences of aging result from attacks by radicals generated primarily in the cell mitochondria during normal metabolism. Because of their unstable nature, highly reactive radicals enter into uncontrolled reactions that damage healthy cell tissue. As the damage to proteins, lipids, and nucleic acids in the body accumulates, aging effects ensue. Harman's theory was controversial at the time7 since most scientists thought that fleeting radicals were not likely to have a significant impact on the biochemistry of life. Over half a century of research would prove this notion to be naive. The first-hard evidence that free radicals could play a significant role in biology came in 1968 with the discovery of a specific enzyme, superoxide dismutases (SOD), whose function was the detoxification of the superoxide radical.8 Superoxide is a highly reactive oxygen radical formed by a single electron...

Defining Free Radicals Antioxidants and Related Terms

Beyond the simple small molecular weight radicals, biological reactions can produce many other radicals from biomolecules. For example, phenolic and other aromatic radical molecules as well as superoxide radicals are often formed during xenobiotic metabolism as part of natural detoxification mechanisms depicted in Figure 3.2. The term xenobiotic was coined to cover all organic compounds that were foreign to the organism under study. Pesticides are a common example of a xenobiotic compound. When a foreign molecule that has the potential to be toxic to the body is taken in, xenobiotic metabolism modifies the molecule using a variety of enzymes that expose or add polar groups to it and mark it for removal. Making a molecule more polar makes it more hydrophilic and thus easier to remove from the body. This process sometimes produces free radicals or radicals of the xenobiotic, both of which can cause potential damage. Such activated molecules have also been implicated in cancer etiology....

Epoxide Formation and Hydrolysis

Epoxides formed by oxidation of aromatic rings or alkenes are, in general, chemically reactive and play roles as ultimate electrophiles in various toxification reactions,including necrosis,mutagenesis, carcinogenesis, and teratogenesis (Daly et al., 1972). These active oxiranes are subject to further transformation in the body. Conjugation with a water molecule, that is, hydration, converts epoxides to dihydrodiols. The hydration of an epoxide may proceed nonenzymatically, but the reaction is facilitated by the action of the enzyme epoxide hydrolase (EC, formerly known as epoxide hydratase or epoxide hydrase. Two distinct epoxide hydrolases are known to exist in the cell one in the microsomal fractions and the other in the cytosol. Epoxide hydrolases have dual roles in the ep* de metabolism. In general, the dihydrodiols that result from the oxirane cleavage are less reactive and less toxic than the parent epoxides, and the process hence represents detoxification. Under...

Carriers with Intrinsic Antiinflammatory Activity

AP is a membrane-anchored protein, that can be shed into the general circulation, which was shown to be able to detoxify LPS in vivo through dephosphorylation 114 .This dephos-phorylating activity could be enhanced by increasing the negative charge of the enzyme through succinylation 115 . Using AP as a carrier for anti-inflammatory drugs to KCs, the main site of LPS uptake, it could intrinsically contribute to therapeutic efficacy in cirrhosis through detoxicification of LPS. The LPS-detoxifying activity of KCs in cirrhotic livers is impaired and consequently LPS may promote the fibrotic process 116 .

Introduction Glutathione From Antioxidant to Redox Signal

Glutathione (GSH), the tripeptide Glu-Cys-Gly, is a low molecular weight thiol antioxidant present in high concentrations in most cells, with the exception of some bacteria and amoebae. Due to its thiol features, GSH may give rise to a variety of chemical reactions that are not typical of other nucleophiles, amino or hydroxyl groups (see Chapter 4). In fact, through nucleophilic addition or displacement, oxidation-reduction reactions, thiol disulfide (SH SS) exchange reactions (or thiol disulfide interchange reactions), GSH detoxifies electrophilic and oxidizing agents, preventing their attack on proteins and other macromolecules. The detoxification actions of GSH are often catalyzed by a variety of enzymes (such as glutathione transferase, glyoxalase, glutathione reductase, glutathione peroxidase, glutaredoxin), which form an efficient machinery capable of protecting cells even when GSH levels are low.

Redox in the Intestinal Lumen

Using cysteine directly released from the epithelium or derived from breakdown of GSH released from epithelium 48 . This is likely an important homeostatic response given the potential importance of the luminal GSH system for detoxification, mucus fluidity, and nutrient transport 49 . Unlike the plasma, the Eh of the cysteine cystine pool is more reduced than the GSH GSSG pool 50 . This is unusual in that the data indicate cysteine as the principal reductant to maintain luminal redox rather than GSH, which appears to serve this function at other sites in the body.

Substance Abuse and Dependence

In some cases, detoxification from the substance(s) upon which one is dependent, e.g., alcohol, may be required before the initiation of treatment. The substances abused may be employed to self-medicate one's psychological distress, necessitating psychological along with prudent psychopharmacologic interventions.

Nonreceptormediated Glutamate Neurotoxicity

We suggest that the main consequence of GSH depletion by glutamate is that it renders cells vulnerable to lipid peroxidation (Fig. 3) (120). GSH peroxidase and GSH transferase are important enzymes that utilize GSH to detoxify lipid peroxides (124-126). The decrease in GSH caused by glutamate treatment may leave GSH peroxidase or transferase operating at lower efficiencies, resulting in a buildup of lipid peroxides in the cell membrane. Lipid peroxides can initiate further lipid peroxidation reactions leading to the generation of more lipid peroxides reactions (8) to (11) (55).

Assessing Functional Significance of Polymorphisms In Vivo

Mice carry two homologs of ABCB1 (Abcb1a, Abcb1b), and viable single- (Abcb1a) and double-knockout mice are commercially available (Taconic Laboratories). In addition, triple-knockout (TKO) mice have become available in which homologous genes encoding ABCB1 and ABCC family members have been removed from the mouse genome. An Abcg2 (the mouse homolog of ABCG2) knockout mouse has also become commercially available from Taconic Laboratories, in addition to a triple knockout, null for Abcb1a, Abcb1b and Abcg2. Many have utilized such mice to evaluate the influence of ABC transporters on the pharmacokinetics and toxicity of drugs. Based on data obtained from these mice, ABCB1 has been shown to play a major role in detoxification and serves as a protective barrier against the toxic effects of xenobiotics (71). These knockouts have been used as animal models of compromised blood-brain barrier function (8,72), intestinal drug absorption (73), fetal drug exposure (74), and drug-induced damage...

Introductory Remarks And Scope Of The Chapter

The biological significance and pharmacological effects of members of the endogenous defence against oxidative insults have been reviewed excellently by others, and will not be discussed at length. Thus, the importance of the vitamins E and C as well as the ubiquinols and carotenoids in disease prevention has become widely recognized and is supported by a host of clinical and epidemiological studies. It should be pointed out, though, that the beneficial effects of antioxidant vitamins on, for example, carcinogenesis, atherosclerosis and coronary heart disease suggested by epidemiological studies have still to be confirmed conclusively in controlled trials (Barber and Harris, 1994 Burr, 1994 Elinder and Walldius, 1994 Rautalahti and Huttunen, 1994 van Poppel et al., 1994). The enzyme systems that are devoted to detoxification of reactive and potentially pathological oxygen metabolites (superoxide dismutase, glutathione peroxidase, catalase, etc.) have also been thoroughly treated by...

In vivo problems associated with RTAIT treatment

A systematic study of in vivo lesions induced by RTA was first conducted by Jansen et al. (1982). They found that the LD50 of whole ricin after a single i.p inoculation corresponds to 0.32 g mouse, that of pure native RTA to 466 g mouse. Consequently RTA which is about 1500 times less toxic than ricin cannot be considered as a very toxic drug and if it becomes separated from the antibody of an IT in vivo its toxicity will be very limited. In an experiment of short-term cumulative toxicity over 5-10 days, doses corresponding to the LD50 were 4-5 times lower than a single injection. Histopathological alterations were also noticed by Jansen et al. (1982). After a lag period of about 10 h ricin at an i.v. dose corresponding to its LD50 causes lesions mainly in the reticuloendothelial system (RES) and the vascular system with disseminated intravascular coagulations and changes related to the shock syndrome. Such lesions were particularly apparent on the endothelium, the Kupffer cells of...

Enzymes Performing Amino Acid Conjugates

Balani SK, Zhu T, Yang TJ et al (2002) Effective dosing regimen of 1-aminobenzotriazole for inhibition of antipyrine clearance in rats, dogs, and monkeys. Drug Metab Dispos 30 1059-1062 Barski OA, Tipparaju M, Bhatnagar A (2008) The aldo-keto reductase super-family and its role in drug metabolism and detoxification. Drug Metab Rev 40(4) 553-624 Rostami-Hodjegan A, Tucker GT (2007) Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov 6(2) 140-148 Torres RA, Korzekwa KR, McMasters DR et al (2007) Use of density functional calculations to predict the regioselectivity of drugs and molecules metabolized by aldehyde oxidase. J Med Chem 50 4642-4647 Uchaipichat V, Mackenzie PI, Elliot DJ et al (2006) Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) probes for human udp-glucuronosyltransferases. Drug Metab Dispos...

ROS Generation with Aging and Exercise

In addition to mitochondria, several other cellular sources of ROS production have been identified, including (a) microsomes and cytochrome P450 complex that have a special detoxification function against xenobiotics (b) peroxisomes which produce H2O2 as a byproduct of amino acid oxidation (c) cytosolic and endothelial xanthine oxidase (XO) that catalyzes the formation of 02* and H202 from hypoxanthine and (d) activated neutrophils that infiltrate injured muscle during inflammatory responses. The first two pathways are of relatively lesser importance in skeletal muscle, which contains low microsome and peroxisome contents. The latter two pathways, however, provide important cellular mechanisms for ROS generation under specific physiological and pathological conditions (see below). Integrated cellular sources of ROS generation in skeletal muscle are illustrated in Fig. 6.1.

Vinylidene Chloride VDC

Since these metabolites are detoxified by GSH, liver GSH status is an important factor in the expression of VDC toxicity. Metabolism of VDC was initially represented as a single saturable process in a PBPK model for closed-chamber inhalation exposures of rats (Gargas et al. 1986, 1990). D'Souza and Andersen (1988) developed a more extensive PBPK model for VDC in the rat based on oxidative metabolism of VDC and subsequent GSH detoxification of its metabolite under a variety of experimental conditions. This model successfully predicted concentrations of VDC in the blood, tissue, and exhaled air and also predicted depletion resynthesis of liver GSH levels as a function of exposure concentrations, dose, and route of administration. The amount of VDC metabolized was sensitive to the rate of absorption due to the low blood air partition coefficient of VDC and due to its saturable metabolism. The terminal half-life of VDC in the blood is not representative of metabolism rates...

Dihydropyrimidine Dehydrogenase

Patients with partial deficiency of this enzyme are at risk of developing severe 5-FU-associated toxicity as DPD is responsible for detoxification of pyrimidine-based antimetabolite analogs, such as 5-FU and capecitabine. The onset of toxicity occurs, on average, twice as fast in patients with low DPD activity compared with patients with normal DPD activity (13-16).

[30 Using Genetically Engineered Mice to Study Myocardial Ischemia Reperfusion Injury

Glutathione (GSH) is one of the essential components of myocardial defense against ischemic stress. The presence of GSH ensures the conversion of toxic lipid peroxides into nontoxic products, utilizing the necessary reducing equivalents from the reduced GSH, which becomes oxidized through the action of glutathione peroxidase (GSHPx). GSHPx can detoxify H2O2, which may be produced in the ischemic myocardium from 02 . To define the precise role of this antioxidant enzyme in myocardial protection, transgenic mice overexpressing GSHPx-1 and knockout mice devoid of any copy of the GSHPx-1 gene are produced.

Concepts of Blood Purification

Blood purification within the body is performed by different organs - carbon dioxide is removed by the lungs excess water and products arising from the dietary breakdown of ingested protein and cellular metabolism are removed by the kidney. The liver has a wide range of functions, including detoxification, protein synthesis and production of biochemicals necessary for digestion. Extracorporeal circulatory procedures may be used as a technique to replace or augment a number of these functions. Such techniques rely upon the removal of compounds from the blood by diffusion, convection or adsorption. The most commonly used extracorporeal circulatory process is the replacement or augmentation of kidney function, with around 20,000 patients in the United Kingdom being treated currently. In the United States in 2004 (the most recent year for which complete data are available), 104,364 patients (approximately 0.03 of the US population) began renal replacement therapy however, considerable...

Chemical Chemical Interactions in the Liver

The enhancement or inactivation of enzyme systems that govern xenobiotic metabolism. For example, a compound that induces hepatic cytochrome P450 2E1 (i.e., chronic ethanol treatment) could significantly potentiate the toxicity of a compound that is bioactivated by this enzyme (i.e., acetaminophen, CCI4). Thus, the enhancement of bioactivation by one xenobiotic can result in a greater amount of toxicity caused by another (Sato et al., 1981 Coon et al., 1984). Glutathione represents an endogenous compound capable of altering both the toxicokinetics and the toxicodynamics of a xenobiotic. This three amino acid peptide can alter the toxicokinetics of a chemical by conjugating with it (or its reactive intermediate metabolites) to neutralize its toxic effects. Thereby, the depletion or induction of glutathione can serve to alter chemically induced toxicity through a toxicokinetic mechanism. For example, a chemical that consumes hepatic glutathione (i.e., 1,3-dichloro-benzene) can...

The Interaction of Carbon Tetrachloride and 12Dichlorobenzene Toxicokinetic Antagonism

For both compounds, bioactivation by cytochrome P450 is known to be an important event in the initiation of liver injury (Valentovic et al., 1993a Sipes et al., 1977). Furthermore, these chemicals have been shown to cause damage to hepatocytes in the centrilobu-lar region of several species of animals (Valentovic et al., 1993b). However, unlike CC14,1,2-DCB-induced liver damage is dependent on hepatic glutathione content, which serves to conjugate and detoxify its reactive intermediates (Fisher et al., 1991). This section describes studies examining the interactive hepatotoxicity of 1,2-DCB and CC14 in male Fischer-344 rats.

Cellular and Biochemical Barriers Multidrug Resistance

Once a drug has entered the cell, detoxification mechanisms within the cytoplasm can potentially inactivate cytotoxic drugs. These include the activity of glutathione and the glu-tathione-S-transferase enzyme. At the nuclear level there is a wide variety of proteins available to protect the cell against chemotherapy-induced damage. The topoisomerase enzymes 20 are common targets for cytotoxic drugs. Topoisomerases are nuclear enzymes, which are involved in DNA replication. Inhibitors of the topoisomerase-1 include agents based on the camptothecin structure, topotecan and irinotecan. They stabilize the covalent complex between DNA and topoisomerase-1 resulting in DNA breakdown and finally cell death. Inhibitors of topoisomerase-2 include etoposide, teniposide and doxorubicin.

In The Substantia Nigra Pars Compacta

Other informative models have been used over the years to test whether the different factors presented in Table 1 can actually ignite ROS attack on SNpc DA neurons. For instance, it was shown that stereotaxic injection of synthetic neuromelanin into rodent brains did not cause cell death by itself but potentiated MPTP-induced neurotoxicity (72). One caveat with this study is that the injected synthetic neuromelanin most likely remained in the extracellular space and did not enter the neurons. Thus, based on this work, we cannot exclude neuromelanin as a neurotoxic compound. More importantly, the stereotaxic injection of MPP+ and rotenone, two mitochondrial poisons, produced severe nigrostriatal damage (73), illustrating the importance of mitochondrial impairment in the death of SNpc DA neurons. As critical as ROS-scavenging enzymes appear to be in the detoxification of ROS, it appears that ablation of extracellular and cytosolic SOD or glutathione peroxidase in knockout mice had...

Glutathione STransferase GST

Glutathione S-transferase (GST) represents an integral part of the phase II detoxification system. GST protects cells from oxidative- and chemical-induced toxicity and stress by catalyzing the glutathione conjugation reaction with an electrophilic moiety of lipophilic and often toxic xenobiotics (van der Aar et al,, 1998). In the liver, GST accounts for up to 5 of the total cytosolic proteins.

[39 Chemokine Expression in Transgenic Mice Overproducing Human Glutathione Peroxidases

Free radical reactions and consequent lipid peroxidation are important regulators of cellular functions. Achieving the proper balance between the generation of ROS and the ability of different type of cells to detoxify or respond to ROS might be critical for a successful outcome under stress conditions. Previous animal studies addressing the role of free radicals and antioxidants have used mainly direct injection or infusion of antioxidants oxidants. In most cases, this approach leads only to the modulation of the extracellular ox redox balance, whereas the intracellular level of oxidative stress might be achieved by changing endogenous levels of antioxidant enzymes. When the increasing evidence of the role of ROS, not only as damaging agents, but also as intracellular signaling molecules is taken into account, it is clear that transgenic mice overexpressing antioxidant enzymes, or having these enzymes deleted, represent a new and promising tool for studying the mechanism of injury....

Synthetic Antioxidants

From a medicinal chemical point of view, there are important differences between the two distinct approaches of preventive and chain-terminating antioxidant agents. Firstly, there is no question that the development of enzyme-mimicking low-molecular-weight compounds is a majestic challenge from a mechanistic perspective. It is always going to be difficult to produce substances that efficiently and catalytically reduce and detoxify reactive species such as the superoxide anion, hydrogen peroxide, hypohalites, singlet oxygen and the hydroxyl radical. Such substances, which so far have relied to a large extent on coordination compounds of transition metals, must also be stable enough under in vivo conditions to avoid toxicity problems. An additional difficulty to overcome is to provide a mechanism of action that guarantees that leakage of reactive byproducts or intermediates are minimized. The enzyme mimics, on the other hand, appear perhaps the most promising agents for antioxidant...

P450 And Other Oxygendependent Biotransformations The Janus Facies Of The Aerobic Lifestyle

The dichotomous behavior of oxygen is inherent to its peculiar free-radical nature, which accounts for its prominent role in biological processes. Oxygen is thermodynamically a good oxidizing agent, so that it can be efficiently utilized in metabolic reactions that produce energy, yet it is kinetically inert, implying that it requires catalytic activation. This may not always be under complete control, thus the evolution of systems that utilize the electron-accepting capabilities of oxygen implies the probability of undesired reactions that can damage cells. Very often, whether the oxidative biotransformation results in activation (toxicity) rather than inactivation (detoxification) depends on a very subtle balance of opposite factors subjected to genetically determined or circumstantial changes. These must be investigated and duly considered when looking at the toxicity mechanisms of xenobiotics or other organic substrates, otherwise the interpretation of biological phenomena may be...

Differential Gene Expression in Rat Liver

In addition to a significant down-regulation of the cGPx gene, selenium deficiency alone was accompanied by an increase in the expression of UDP-glucuronosyl-transferase 1 gene and bilirubin UDP-glucuronosyltransferase isoenzyme 2 gene (Table 15.1). These two genes encode for enzymes that have an important function in the detoxification of xenobiotics in liver. Similarly, rat liver cytochrome P45Q4B1, which is also involved in xenobiotic metabolism and inducible by glucocorticoids, was induced 2.3-fold. The mRNA levels of arachidonate 12-lipoxygenase (ALOX 12) were 2.4-fold higher in selenium-deficient rats than in controls. It has been shown that ALOX 12 and PHGPx are opposing enzymes balancing the intracellular concentration of hydroperoxy lipids an inhibition of PHGPx activity increases the enzymatic catalysis of ALOX 12 (20). Peroxide detoxification Peroxide detoxification Detoxification, export of leukotriene C4 Overall in this in vivo study, vitamin E deficiency alone did not...

APP modulation of Cu homeostasis

How APP (and APLP2) modulate Cu in vivo is not known, although the Cu reductase activity of APP (and AP) is consistent with the activity of well-characterized Cu transporters such as Fre1 in yeast 127 . The APP N-terminal CuBD has a 3D structure very similar to Cu chaperones, supporting a role for APP in cellular Cu trafficking. APP molecules may also be released from the cell surface by a-secretase, thus removing excess Cu from the cell. This is supported by the report that liver contained an 80 increase in Cu in APPo o mice compared to controls 123 . The liver is an important site of Cu homeostasis in mammals. Further evidence for an APP Cu-detoxification model comes from studies on APP over-expressing cells. Borchardt et al. 128 found that exposure of these cells to increased Cu switched APP metabolism from the AP secretory pathway to a-scretase mediated release of APP. The increased secretion of APP may have increased the cell's capacity to off-load excess Cu although this has yet...

Chloramphenicol Acetyl Transferase Secreted Placental Alkaline Phosphatase PGalactosidase

The longest-established reporter gene system is the bacterial enzyme chlorampheni-col acetyl transferase (CAT).24 CAT can detoxify chloramphenicol (an inhibitor of prokaryotic protein synthesis) by catalyzing the transfer of acetyl moieties from acetyl CoA to the 3-hydroxyl position of chloramphenicol. The enzyme is stable, and there is no endogenous expression in mammalian cells. However, it has a rather high detection limit of 5 X 107 molecules and a low dynamic range. Furthermore, it is a radioactive, labor-intensive assay, which makes it difficult to automate for HTS. Due to these disadvantages, its present use in drug discovery is rather limited. The activity of SEAP (secreted placental alkaline phosphatase),25 which is a mutated form of the human placental enzyme, can be monitored easily by colorimetric, fluorescent, and chemiluminescent detection systems. The chemiluminescence assay is based on the use of 1,2-dioxetane substrates. Its sensitivity in several orders of magnitude...

Ketogenic Diet And Amino Acid Transport

This adaptation might be an enhanced capacity to dispose of glutamate that had been released into the synaptic cleft. In effect, the brain would detoxify extracellular glutamate not simply by swiftly removing it from the synapse into astrocytes and then converting it to glutamine, but by exporting the latter into the blood rather than exporting it back to neurons (Fig. 2). This loss of glutamine would quickly be compensated by the transamination of the newly imported leucine (Fig. 7). However, during periods of enhanced glutamate release from neurons, a phenomenon that characterizes seizure activity, the system would have at its disposal a new mechanism for the removal of external glutamate.

Contribution Of Amyloidp Peptide To Oxidative Stress And Neuronal Degeneration In Ad

Important antioxidant that can bind and detoxify 4-hydroxynonenal, and thereby protects neurons against the toxicities of AP, Fe2+, and hydroxynonenal (3,30). 4-Hydroxynonenal may play a particularly prominent role in a form of cell death called apoptosis in which a cell shrinks, and nuclear chromatin condensation and DNA fragmentation occurs (30). Accordingly, antioxidants that suppress membrane lipid peroxidation, including vitamin E, propyl gallate, 17P-estradiol, and uric acid, prevent Ap-induced apoptosis (3-7,10,25-31).

Treatment of patients with hepatic coma

However, liver is a complex organ with many other functions besides detoxification. Thus, a detoxifier alone cannot fully support liver function. As mentioned in the previous chapter, hemoperfusion could play an important role in removing hepatic toxins to allow the use of artificial cells containing hepatocytes and stem cells for liver regeneration.

Oxidative Stress as a Mediator and Inducer of Apoptosis

One promising approach employs superoxide dismutase (SOD) inhibitors, such as 2-methoxyestradiol (2-ME). These compounds prevent SOD from detoxifying superoxide radicals. The subsequent build-up of these radicals may kill the affected cell. Since some cancer cells possess higher levels of oxidative stress compared to normal cells, inhibiting such antioxidant enzymes may even provide cancer cell selective effects. While SOD is not the most potent of antioxidants -after all, it generates H2O2 as part of O2 detoxification - other antioxidant enzymes, such as glutathione peroxidase (GPx), provide rather interesting targets for intervention into intracellular redox control.

Other Antioxidant Genes Or Genes Regulated By An Altered Redox State On Chromosome

The CBR gene, coding for the enzyme carbonyl reductase, is another gene on chromosome 21 (at 21q22.12) that may have an antioxidant function. Carbonyl reductase is a NADPH-dependent oxidoreductase with a broad specificity for carbonyl compounds (Wermuth, 1982). It may therefore play a role in the detoxification of oxidized compounds. Indeed, cells overexpressing carbonyl reductase display an increased resistance to paraquat, a potent herbicide whose toxicity is thought to result from increased lipid peroxidation and toxic carbonyl products (Kelner et al., 1997). However, the significance of the overexpression of this antioxidant enzyme in DS still remains to be elucidated.

Factors Impacting Ocular Transporters And Metabolizing Enzymes

Zhao and Shichi were the first to demonstrate specific cytochrome P450 isoform induction in a specific ocular tissue (27). Following intraperitoneal P-naphthoflavone treatment in mice, CYP1A1 1A2 expression was induced in the ciliary non-pigmented epithelium, choroid, retinal pigmented epithelium, cornea epithelium, and iris epithelium. The authors proposed that, since the ciliary epithelium is involved in aqueous humor formation by acting as a metabolic ultrafiltration system for blood plasma, then drug-metabolizing enzymes in these tissues may play a critical role in metabolic detoxification of plasma prior to its secretion as aqueous humor.

Quantitative Copperion Homeostasis

Organisms such as yeast have a remarkable ability to adapt to drastically varying copper-ion conditions. Yeast gene expression differs greatly under different copper-ion conditions (30), which implies that yeast can detect the changes in copper-ion concentrations. The transcription factor Mac1p plays a pivotal role in yeast copper-ion homeostasis. Mac1p controls copper-ion uptake by regulating the expression of genes encoding high-affinity copper-ion transporters CTR1 and CTR3 (29,31-38). Mac1p has also been shown to participate directly in copper-ion detoxification through a mechanism independent of CTR1 and CTR3 (39). We have also found that Mac1p might regulate the degradation of Ctr1p in response to toxic copper levels, by a yet to be explored mechanism independent of its regulatory role in CTR1 transcription (Zhu, unpublished results 40). A long-standing question in understanding how Mac1p senses copper ions and regulates CTR1 and CTR3 transcription was whether copper ions affect...

Yeast Copperiron Link

Mac1p and Ace1p are the two copper-responsive transcriptional activators in S. cerevisiae (2,9,10). Under copper-deficient conditions, Mac1p activates the expression of six genes, CTR1, CTR3, FRE1, FRE7, YFR055w, and YJL217w. With elevated copper levels, Ace1p activates the expression of copper-detoxification proteins, Cup1p and Crs5p.

Mammalian Copperiron Link

In mammals at a whole-body level, copper absorption from the small intestine is, to some extent, regulated, with increased uptake when the animal is copper deficient and decreased uptake when the diet is adequate in copper (82). Details of the molecular mechanisms regulating absorption remain to be elucidated. The control of copper excretion, which is also an important part of the protection against excess copper exposure, is regulated by the liver, with excess copper being disposed of through the bile (83). Within the cell, excess copper is detoxified by at least two mechanisms sequestration by metal-binding proteins such as metallothioneins (MT) and enhanced export by the copper ATPases, MNK, and WND (84). Although a definitive biological role for MTs remains elusive despite years of research, MTs are known to be small cysteine-rich proteins that bind heavy metals, including copper, zinc, and cadmium, through cysteine thiolates (85,86). There are l7 genes encoding four isoforms of...

Copperiron Link In Photosynthetic Organisms

Besides having the same copper and iron requirements as human and yeast cells, photosynthetic organisms have additional requirements for these metals in the plastid, where they are utilized as the redox active cofactors in many metabolic processes, including, in particular, the proteins involved in photosynthetic electron transfer in the chloroplast. Iron-containing cytochromes, Fe-S centers (> 20 atoms per PSII PSI unit), and copper-requiring plastocyanin are abundant proteins in photosynthetic organisms. Metal metabolism in this context presumably requires a completely separate set of factors in addition to those required for cellular and mitochondrial iron and copper metabolism. A further challenge for photosynthetic organisms is that biologically useful levels of soil copper and iron are low. The variability in the mineral composition of soils means that for plants to survive and grow they must adapt to the variation in supply of copper and iron. As with yeast and humans, the...

Manipulating Resistance to Oxidants Dietary Restriction

Dietary restriction regimens display a well-documented ability to increase longevity and decrease morbidity in rodents (Kristal and Yu, 1994 Shimokawa and Higami, 1994). One of the most striking effects of dietary restriction (DR) is its ability to decrease oxidative damage to critical targets, including mitochondria (Weindruch et al, 1980 Laganiere and Yu, 1989 Yu et al, 1992 Sohal et al, 1994 Yu, 1996). Mitochondria from dietary restricted animals have lower basal levels of lipid peroxidation, generate less lipid peroxidation on challenge, and detoxify harmful lipid peroxidation by-products at greater rates than those from ad libitum-ied rats (Laganiere and Yu, 1987 Chen and Yu, 1996). Mitochondria from dietary restricted animals also maintain membrane structure and function (e.g., fluidity and lipid composition) later in life than those from ad libitum-ied rats (Yu et al, 1992). Further work shows that steady-state levels of 8-hydroxydeoxygu-anosine (Chung et al, 1992) and...

Deficiency Of Striatal Glutathione In

Y-Glutamyl has a major role in metabolism of leukotrienes, estrogens, and prostaglandins, and detoxification of xenobiotics in the brain. The enzymes of the y-glutamyl cycle are abundant in the choroid plexus (73), suggesting that the cycle plays a role in transporting essential substances into the brain, and recycling of glutathione in cerebrospinal fluid (74). y-Glutamyltranspeptidase is present in capillaries, astrocytes, and neurons (75). In addition, glutathione transporters do exist, which plays a role in its homeostasis (76).

Viability and Functionality of Liver Slices

Because these different viability tests all reflect different aspects of cell viability, the choice of test depends on the aim of the study. For toxicity studies where biotransformation is an important bioactivation or detoxification step, metabolic function tests should be included to judge the validity of the method, whereas viability tests are needed to assess toxic effects. Both positive and negative controls should be included in such studies. When human liver is used, the characterization of metabolic activity is especially important because of the large inter-individual variability associated with this property 75 .

Glucuronosyltransferase Polymorphism and Irinotecan

A polymorphism resulting from a mutated promoter of UGT1A1, termed UGT1A1*28, is responsible for the impaired glucuronosyltransferase activity of UGT1A1. This polymorphism is associated with Gilbert's syndrome, a relatively mild, nonpathogenic, hyperbilirubinemic, often undiagnosed disorder that occurs in up to 19 of individuals. Biotransformation of irinotecan, an anticancer prodrug, involves its sequential conversion by carboxylesterase to SN-38, and subsequently detoxification to the pharmacologically inactive SN-38 glucuronide. SN-38 is a potent topoisomerase inhibitor, but SN-38 glucuronide formation is impaired by the polymorphism of UGT1A1*28. This polymorphism is due to an additional TA repeat in the TATA sequence of the UGT1A1 promoter (TA)7TAA, instead of (TA)6TAA . The frequency of the 7 7 polymorphism in Caucasians is 20 . Persons with this polymorphism are predisposed to severe grades of diarrhea and leukopenia. The UGT1A1*28 polymorphism may serve as a marker predictive...

Substance Dependent and Substance Abusing Patients

The patient's detoxification from the substance(s) on which he or she is dependent might be required before the initiation of treatment. An overly aggressive detoxification can be particularly distressing for patients, perhaps resulting in the inclination to abandon treatment detoxification. In addition, during the course of detoxification, it could be imperative to undertake simultaneous measures to mitigate pain otherwise, the distress to which the patient is subjected might be too great, and the patient may develop intense fears that his or her pain will be unrecognized and inadequately treated. Detoxification is required for the patient who is alcohol dependent. In some cases, the substances abused might have appeal as a means of controlling one's psychological distress (e.g., cannabis and benzodiazepine abuse to address underlying anxiety or ineffective coping). Hence, psychological interventions, along with prudent psychopharmacologic interventions for underlying psychiatric...

Prescribing Opioids The Controlled Substances Act from 1979

However, federal law does prohibit the use of opioids to treat addiction without a separate DEA registration in a Narcotic Treatment Program (NTP) 39 . So any registrant can treat pain with opioids in an addicted patient they can detox or maintain addiction in a hospital if the addict is admitted for reasons other than addiction, such as a motor vehicle accident, but once the addicted patient is an outpatient, a physician cannot maintain their addicted state outside of a Narcotic Treatment Program.

Buprenorphine Therapy

Buprenorphine as an alternative to methadone in pregnancy has been validated by several naturalistic studies in France, where outpatient physicians can treat with buprenorphine without specialized training up to 70,000 patients annually have received the medication on an outpatient basis since the 1996 liberalization of policies (Auriacombe et al. 2004). Despite positive findings for buprenorphine in pregnancy by several French and some American studies (Fischer et al. 2006, Auriacombe et al. 1999), one Finnish study described greater severity of the neonatal abstinence syndrome and higher rates of SIDS (Kahila et al. 2007). Naltrexone is thought to possibly play a role in relapse prevention, and it has been utilized for maintenance after an initial taper with buprenorphine. Naltrexone was used, in one small Australian study, for a detoxification protocol during pregnancy and showed favorable results. Naltrexone implant is currently being studied and initial results seem promising.

Table 93 Pain management in patients with substance abuse dependence

Address detoxification and rehabilitation needs for ongoing substance abuse Assess adherence with substance abuse treatment programs Consider making opioid analgesia contingent on verifiable participation in addiction recovery treatment program Assess for signs of relapse Periodic, random urine toxicology screens Frequent follow-up and monitoring Assessment of overall functioning In cases of iatrogenic drug dependence, the patient may require careful systematic detoxification from the medications on which he or she has become dependent. The patient's functioning might then improve. Behavioral measures could be required to de-emphasize the focus on somatic complaints. Cognitive-behavioral interventions might be required to address ineffective coping, troublesome cognitive appraisals, and adverse emotions. It is these emotions the patient has been trying to treat with the medications prescribed.

Therapeutic Potential of Radical Scavengers in Parkinsons Disease

Free radicals and other reactive oxygen species (ROS) are formed as side products of oxygen metabolism in every aerobic organism. Acceptance of a single electron by an oxygen molecule forms the superoxide radical, O2, which has an unpaired electron. Superoxide is formed in vivo in a variety of ways. A major source is the mitochondrial electron transport chain. The electrons passing through this chain are captured by O2 leading to water as the end-product. Because O2 accepts one electron at a time, O2 is formed. Efficient antioxidant systems have been developed to prevent uncontrolled free radical formation before they can cause damage to cellular structures (Fig. 1). Superoxide dismutase is involved in detoxification by dismutation of O2- to hydrogen peroxide (H2O2), which is rapidly converted to water by the reducing enzymes catalase or glutathione peroxidase (1-3). When the balance between the production of oxygen-derived species, such as O2- and H2O2, and antioxidant defenses...

Overview Of Bioactivation

Reactive metabolites have been implicated in some cases of toxicity, but the link between reactive metabolites and toxicity is complex and in most cases difficult to establish. The liver is frequently the target organ of reactive metabolites because of the high levels of drug and drug metabolizing enzymes in the liver. A well-established example is the severe hepatoxicity associated with bioactivation of acetaminophen to N-acetyl-p-quinoneimine (NAPQI) at high doses. After saturating the detoxification conju-gative pathways and depleting intracellular glutathione (GSH), NAPQI reacts with critical cellular protein nucleophiles and produces cellular necrosis (see Fig. 6.2). Detoxification Detoxification

Plant Cell Homeostatic Copper Networks

Although direct copper binding to metallothioneins has not been demonstrated in plants yet, there are at least two copper-regulated MT gene families in Arabidopsis (Fig. 1) whose function as copper chelators is mainly accepted based on functional complementation of the yeast mutant Acupl (20). The pattern of MT expression differs depending on the member of the family, but they accumulate in leaf trichomes, suggesting a detoxification mechanism similar to the secretory strategy used by halo-phyte plants that extrude salts (23). To date, no cis metalloregulatory elements, such as the metal-responsive element (MRE) sequences from yeast, nor other regulatory elements, have been found in the promoters of these genes (21). On the other hand, Arabidopsis plants transformed with a chimeric construct, based on a reporter gene under the control of the yeast metallothionein CUP1 promoter, do not respond to copper exposure (24). This result suggests that plants possess a copper-sensor regulatory...

Other Hormone Axes and Possible Levels of Disruption

Among the nuclear receptor superfamily there are receptors with unidentified ligands (hormones) called orphan receptors 108 . Some of these orphan receptors are now receiving names as their ligands are discovered. For example, the steroid-xenobiotic receptor (SXR) is a nuclear receptor that has been shown to activate transcription when bound by certain native steroid hormones or xenobiotics. SXR appears to induce transcription of xenobiotic and steroid hormone detoxification and metabolizing enzymes 37 . Steroidogenic factor-1 (SF-1) is still an orphan receptor because its ligand remains unidentified. However, it has been associated with regulation of some P450 steroidogenic enzymes, and more recently was shown to play an important role in the development of the gonad and adrenal glands in mice 109 and gonadal sex-differentiation in the chicken 110 . The obvious influence of former and present orphan receptors on development and reproduction in lab animals strongly

Analogues as Probes of Physiological and Pathological Roles

Within this protective context, Sx- expression is a part of a number of different adaptive cellular responses (e.g., amino acid starvation, ox-idative stress, toxic exposure) that are under transcriptional control regulated by genomic cis-elements. In the most thoroughly studied cases, exposure to electrophiles and or increased oxidative stress activates transcription factors (e.g., Nrf2) that bind to electrophilic-responsive elements (EpRE) antioxidant-responsive elements (ARE) and result in the up-regulation of proteins presumed critical to detoxification and or antioxidant defense mechanisms, including GSH transferase, y-glutamylcysteine synthetase, NAD(P)H quinone reductase, heme-oxygenase 1 and Sx- 166-169 . The transporter is also present (and inducible) at the blood-brain barrier, where it may serve as a point of entry not only for L-Cys2, but also structurally related drugs and neurotoxins (e.g., -L-ODAP, see above) 124,151, 164,170 . Surprisingly, the level of Sx--mediated...

The Regulation of OATPsOatps

The regulation of OATP Oatp isoform expression and the functional kinetics of each transporter can occur at both the transcriptional and posttranscriptional levels (Hagenbuch and Meier, 2003). Several studies have investigated the tran-scriptional regulation of OATP Oatp isoforms and various control elements were identified (Rausch-Derra et al., 2001 Staudinger et al., 2001 Guo et al., 2002b). Increased Oatp2 mRNA and protein expression were observed from livers of rats treated with pregnenolone-16a-carbonitrile (PCN) (Rausch-Derra et al., 2001). Pregnane X receptors (PXR) were suggested to play a major role in this PCN induction. Oatp2 expression was strongly induced by PCN treatment in the PXR+ + mice, but not in the PXR ' mice (Staudinger et al., 2001). Furthermore, several PXR response elements have been identified on the rat Oatp2 promoter (Guo et al., 2002b). Since PXR is one of the key regulators of cytochrome P450 3A (CYP3A) (Luo et al., 2004), concomitant PXR-dependent...

Miscellaneous Agents For Chemoprevention

1,2-Dithiol-3-thiones, reported constituents of cruciferous vegetables, are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, and chemoprotective activities. In this context, oltipraz, which was originally developed as an antischistosomal agent, was found to protect against chemically induced carcinogens in the lung, stomach, colon, and urinary bladder in animals.33 Its utility as a cancer chemopreventive agent is thought to depend on the induction of enzymes involved in Phase II xenobiotic detoxification.34 Polycyclic aromatic hydrocarbons, N-nitrosamines, and other compounds produce electrophilic carcinogenic metabolites. Thus, the fungal toxic secondary metabolite aflatoxin B1 (AFB1) may contaminate food and by epoxydation of a furane double bond by a P450 cytochrome (Fig. 13.5) give carcinogenic compounds that are inactivated by glutathione addition catalyzed by glutathione S (GSH)-transferase (see Section 2.1 of Chapter 11). Oltipraz stimulates...

Dietary Restriction and Reduction in Oxidative Stress

Although there are probably many such issues, we will focus on two selected examples methionine and unsaturated fatty acids. Common wisdom has it that reducing agents, such as cysteine (e.g. in form of N-acetyl-cysteine), ascorbic acid, vitamin E and also the sulfide methionine are good for the human body, since they can detoxify reactive species, such as ROS, by reducing these species to harmless substances, such as water. Although some of these substances may be one-way reducing agents, which are sacrificed in the process, they nonetheless appear to serve a purpose as health protective antioxidants. Similar considerations apply to fatty acids, where popular perception equates a high degree of unsaturation (in cis-unsaturated fatty acids) with increased health benefits. Consumption of unsaturated fatty acids may, for instance, result in lowering levels of low-density lipoprotein (LDL) and cholesterol and hence prevent damage to the cardiovascular system.

Mechanism Of Action

Moving from intestine to liver and concentrating in liver cells. Protein synthesis is induced in the liver by silybin, whose steroid structure stimulates both DNA and RNA synthesis. Through these activities, the regenerative capacity of the liver is activated. Silymarin is reported to alter the outer cell membrane structure of liver cells, blocking entrance of toxic substances into the cell. This blockage is so pronounced that it can reduce the death rate from Amanita phal-loides poisoning. Silymarin's effect can be explained by its antioxidant properties it scavenges free radicals. By this effect, the level of intracellular glutathione rises, becoming available for other detoxification reactions. Silybin inhibits enzymes such as lipoxygenase,66 blocking peroxidation of fatty acids and membrane lipid damage. Studies also show that silymarin protects the liver from amitriptyline, nor-triptyline, carbon tetrachloride, and cisplatin. When treated, patients with alcoholic cirrhosis showed...

Nonprotoplasmic Ergastic Cell Contents

Cluster Raphides From Crystal Cells

Calcium Oxalate Many plants detoxify soluble oxalic acid as insoluble calcium salts. Calcium oxalate crystallizes in characteristic forms these shapes can be very important for diagnostic purposes (Figures 7.12 and 7.13). The exact crystallographic forms of these crystals are determined by measuring their angles. This is difficult and many technical and nontechnical terms are used to describe them. Calcium oxalate crystals are birefractive (birefringent), which makes them visible in polarized light (Figure 7.13a-c). Druses are clusters of calcium oxalate crystals that are shaped like diamonds (Figure 7.13a) raphides are composed of slender, needle-like crystals (Figure 7.13b). Prismatic crystals are rhomboidal in shape

Tetrachloroethylene PERC

PERC is widely used dry cleaning and as a metal degreasing solvent. It is a hazardous air pollutant, a common contaminant at Superfund waste sites, and a surface-water and groundwater pollutant. The rodent carcinogenicity of PERC in the liver is considered to result from the generation of reactive intermediates during its metabolism (Clewell et al. 2004). As in the case of TCE, the pathways for PERC bioac-tivation and detoxification are complex and several of the enzymes involved exhibit sex- and species-dependent differences. Consequently, it has been suggested that information about species differences in multiple pathways would be necessary to extrapolate results from experimental animals to humans with certainty (Lash and Parker 2001). However, the metabolism of PERC has not been as extensively studied as it has for TCE as a result, the PBPK models for PERC have been limited to descriptions of the parent chemical and its major metabolite, TCA. Although the oxidative rate of...

Oxygen and Nitrogen Free Radicals

Not counting hydrocarbons, there is a greater diversity of molecules with oxygen than with carbon. Dioxygen or diatomic oxygen (O2) is a diradical in its ground state with low solubility in aqueous solutions, that reacts in a kinetically peculiar fashion in oxidation reactions, and forms toxic byproducts as it gets reduced. As a result, all life forms evolved ways to deal with these problems, including ways to increase its solubility (with dioxygen binding and transport proteins), and enzymes (that could activate it kinetically and also detoxify oxygen by-products). It is important to understand the properties of dioxy-gen since oxidation reactions using it, power not only our bodies but our entire civilization.

Microbial Peroxiredoxins

Proteins strikingly homologous (30-70 identity) to E. coli AhpC, p20, or BCP are commonly found in other bacteria (not discussed here) such as Helicobacter pylori and S. typhimurium. Bacterial BCP and p20 contain only one cysteine. By this criterion, they are more similar to the monocysteine peroxiredoxins (lCPrx) found in higher organisms (Kang et al., 1998b). In contrast, AhpC proteins have two conserved cysteines and are more closely related to the TSA subfamily. Notably, not all bacteria have the three types of peroxiredoxins several have only one or two. For example, only one peroxiredoxin (lCPrx) is found in the three archaea (Meth ano coccus jannaschii, Methanobacterium thermoautotrophicum, and Archaeoglobus fulgidis) with complete genomes sequence. In contrast, Bacillus subtilis, the cyanobacterium Synechocystis sp., and the hyperthermophi-lic bacterium Aquifex aeolicus encode four peroxiredoxins in their genome (Figs. 1 and 2). Conceivably, the presence of multiple...

O Sites Of Drug Biotransformation

Although biotransformation reactions may occur in many tissues, the liver is, by far, the most important organ in drug metabolism and detoxification of endogenous and exogenous compounds.13 Another important site, especially for orally administered drugs, is the intestinal mucosa. The latter contains the CYP3A4 isozyme (see discussion on cytochrome nomenclature) and P-glycoprotein that can capture the drug and secrete it back into the intestinal tract. In contrast, the liver, a well-perfused organ, is particularly rich in almost all of the drug-metabolizing enzymes discussed in this chapter. Orally administered drugs that are absorbed into the bloodstream through the GI tract must pass through the liver before being further distributed into body compartments. Therefore, they are susceptible to hepatic metabolism known as the first-pass effect before reaching the systemic circulation. Depending on the drug, this metabolism can sometimes be quite significant and results in decreased...

Muscarinic M5 Receptors

These brain areas play a major role in the rewarding effects of several drugs of abuse. In muscarinic M5-deficient mice stimulation of the laterodorsal tegmental area, which provides major cholinergic input to the ventral tegmental area dopamineric neurons, is markedly disrupted. The potential of selective muscarinic M5 blockade as an approach to narcotic addiction corroborates to the extensive use of scopolamine and extracted alkaloids in the detoxification of heroin addiction (Basile et al. 2002). Transgenic mice lacking the M5 receptor do not exhibit increased basal locomotor activity. Several studies indicate that muscarinic M5 knockout mice are less sensitive to actions of addictive drugs, such as morphine or cocaine (Fink-Jensen et al. 2003). However, these data have recently been disputed in that augmented hyperactivity effects of amphetamine, but not cocaine, were seen, as well as an increase in the release of dopamine from the nucleus accumbens in mice M5 knockouts (Steidl...

Hypersensitivity Reaction Of Phenytoin

Hypersensitivity reactions (idiosyncratic toxicity) to phenyt-oin and other aromatic AEDs in susceptible individuals are believed to stem from the reactions of these reactive intermediates (i.e., arene oxide, catechol, or o-quinone) with hepatic enzymes or other cellular proteins forming covalently bonded haptens.45 The reactive intermediate, arene oxide, is deactivated by either epoxide hydrolase to dihydrodiol (a major urinary metabolite) or by the action of GSH and glu-tathione transferase. It has also been suspected that these reactive arene oxides or epoxides mediate the teratogenicity of phenytoin and other AEDs. Recent studies indicate that epoxide hydrolase might be useful as a biomarker for prenatal determination of risk of fetal hydantoin syndrome.46,47 Again, glutathione and epoxide hydrolase are important for detoxification of these reactive metabolites. Furthermore, a normal level of COMT in the liver or kidneys also greatly reduces the amount of catechol, which can be...

B12dependent reductive dehalogenases

Anaerobic microbes containing B12-dependent reductive dehalogenases play an important role in the detoxification of aromatic and aliphatic chlorinated organ-ics, which include compounds on the EPA priority pollutant list such as chlorinated phenols, chlorinated ethenes, andPCBs (146, 147). Exposure to these compounds induces a host of genes involved in removing the chloride ion. Both aerobic and anaerobic microbes can perform dehalogenation however, anaerobic bacteria are more efficient in removing halogen atoms from polyhalogenated compounds (148). Desulfomonile tiedjei was the first dehalogenating anaerobe to be isolated and characterized (149), and 20 strains of anaerobic organisms capable of reductive dehalogenation have so far been isolated, including Desul-fomonile, Desulfitobacterium, and Dehalobacter.

Vitamin C Transporters In The Retina

From the subretinal space via this Na+-coupled transporter. RPE cells may accumulate reduced ascorbate for use as a protective agent against oxidative damage. It is interesting that these cells express GLUT1 not only on the basolateral membrane, but also on the apical membrane. This raises the possibility that DHAA, which comes into the cells from the choroidal circulation via GLUT1 in the basolateral membrane, and which gets generated inside the cells from reduced ascorbate during the detoxification reactions, may exit the cells via GLUT1 in the apical membrane to enter the subretinal space. Thus, RPE cells may serve as a supplier of DHAA to the neural retina. Neural retina consists of several neuronal cell types (photoreceptor cells, ganglion c ells, amacrine cells, bipolar cells, and horizontal cells) and the glial M ller cells. M antych et al. (51) have performed detailed immunolocalization studies to delineate the expression of GLUT isoforms in the retina. Their studies showed...

Why Carboxylation And Why CoM

Epoxyalkanes are highly reactive molecules and, when formed as metabolic intermediates, should not be allowed to accumulate to toxic levels. As a reflection of this, EaCoMT has a very high affinity for epoxypropane (Km, epoxypropane 18 M) and is expressed at high levels (4 of soluble protein) in propylene-grown cell cultures (27, 38). In fact, epoxypropane does not accumulate to detectable levels in cells grown with propylene as the carbon source (33). In contrast to EaCoMT, epoxide-utilizing enzymes involved in detoxification generally have lower affinities and broader substrate specificities. Glutathione-S-transferases, for example, use a variety of electrophiles other than epoxides as substrates (9), although epoxide hydrolases generally have broader substrate specificities than EaCoMT (10). efficient and stereoselective dehydrogenation and reductive carboxylation in the subsequent steps (Figure 4). The sulfonate moiety of CoM provides a selective handle for recognition by the...

Summary And Conclusion

In the foregoing discussion we have tried to define the nature of OxS and then, using that definition, to assess the status of OxS in diabetes. Based on analysis of various biomarkers of OxS in long-lived proteins, we conclude that OxS is not overtly or systemically increased in diabetes, except at later stages in the development of complications. Metabolic derangements in diabetes lead to an increase in concentration of oxidizable substrates and compromised detoxification pathways. The resulting increase in reactive carbonyls in tissues, known as carbonyl stress, leads directly to increased chemical modification of proteins in diabetes. Efforts directed at decreasing substrate concentration (maintenance of euglycemia and normolipidemia), bolstering detoxification pathways (GSH precursors or enhancers), and trapping reactive carbonyl species (AGE inhibitors, carbonyl traps) represent reasonable therapeutic approaches for limiting the chemical modification and crosslinking of proteins...

Regulation of mRNA Translation and Stability in Iron Metabolism Is there a Redox Switch

Due to its capacity to donate or accept electrons, iron was selected since the earliest times of natural evolution for redox reactions in living organisms. Thus, iron in heme, in iron-sulfur clusters or directly bound to proteins is a constituent of many essential proteins with functions in oxygen transport, energy metabolism, electron transfer, deoxynucleotide synthesis or detoxification. Its presence in the active sites of numerous enzymes implies that cells must have a sufficient pool of free iron available for protein Unless incorporated into proteins, divalent cytoplasmic iron on transit is potentially toxic as it catalyzes in the presence of H202 the formation of hydroxyl radicals that damage DNA, proteins and membrane lipids. In order to diminish excess cytoplasmic iron, cells synthesize H and L chain ferritin subunits that assemble to hollow protein shells of 24 subunits into which up to 3500 ions of iron get deposited (reviewed by Harrison.10) Ferritin can, therefore, be...

Formation of Lipid Hydroperoxides

Lipid hydroperoxides are formed nonenzymatically by reactive oxygen species (ROS) such as superoxide (O2 -), peroxide (O22-), and hydroxyl radical (HO). The endogenous pathways for ROS generation include normal mitochondrial aerobic respiration, phagocytosis of bacteria or virus-containing cells, peroxisomal-mediated degradation of fatty acids, and cytochrome P450-mediated metabolism of xenobiotics DNA (26). Mixtures of vitamin C and transition metal ions (27), and the conversion of catechols to quinones (28) can also cause ROS formation from molecular oxygen. Antioxidant defense systems in vivo that can detoxify ROS include the following superoxide dis-

Biological Reactivity Formation And Metabolism Of Epoxides

Epoxides are formed biogenically by the epoxida-tion of alkenes in reactions catalyzed by a number of enzymes with mono-oxygenase activity. These epoxidation reactions may be catalyzed fortuitously (i.e., in place of the natural oxygenase substrate), as the first step in detoxification of alkenes (as in the case of cytochrome P450) (6) or as the first step in the utilization of alkenes as primary carbon and energy sources for growth (7, 8). Many organisms have detoxification enzymes that catalyze the transformation of epoxides to less toxic products, specifically, glutathione S-transferases, which form glutathione conjugates of epoxides (Figure 1a) (9), and epoxide hydrolases, which hydrate epoxides to the corresponding dihydrodiols (Figure 1 b) (10). Epoxide hydrolases initiate epoxide catabolism in certain bacteria that grow using epoxypropane or epichlorohydrin (3-chloroepoxypropane) as carbon sources (11, 12). In the case of bacteria that grow using...

Toxicity and Carcinogenicity of the Aromatic Hydrocarbons

When benzene is inhaled, it is distributed in four principal areas of the human organism the liver, tissues with increased blood supply (brain, kidney, heart, spleen), tissues with poor blood supply (muscle, skin) and fat tissue 8 . Benzene is taken up through the lungs, the gastrointestinal system and the skin. Its metabolism takes place mainly in the liver and secondarily, in the bone marrow, where benzene exerts its toxicity. Its metabolism is dose-dependent and follows two pathways the ring hydroxylation pathway and the open ring pathway 9-11 . Hydroxylated metabolites form glycuronides or sulfuric conjugations which are excreted in the urine as detoxification products. Sulfuric conjugations lead to the elimination of the toxic metabolites. The open ring pathway leads to the formation of toxic by-products, trans, trans-myconaldehyde and myconic acid which are also detoxified and excreted in the urine 12 . Benzene metabolism takes place quickly in the liver tissue where it is...

Cellular Copper Homeostasis

Evolved to handle copper is the dual nature of copper in biological systems Copper is both an essential cofactor for various Cu-dependent enzymes and a potential pro-oxidant. To function normally and to protect itself from potential damage a cell must be able to sense and respond to changes in intracellular copper levels. Different mechanisms will be activated in response to deficiency or excess as cells adopt an acquisition or detoxification mode depending on their copper status. Whole-body copper homeostasis depends on these mechanisms, which are modified in cells such as the intestinal enterocyte (acquisition) or the hepatocyte (detoxification). These modifications are discussed in more detail in Section 2.3. (see Figs. 3 and 4).

Proapoptotic Properties Of Antioxidants

Apart from ROS-detoxifying effects, antioxidant molecules may function as regulators of signal transduction pathways. For example, the possibility that N-acetylcysteine, unlike other antioxidants, suppresses neuronal apoptosis by regulating cell cycle progression has been proposed (Ferrari et al., 1995). In several other cases, however, potentiation of apoptosis by antioxidants has been reported to occur by pathways that are apparently independent of ROS detoxification. N-Acetylcysteine has been shown to elevate p53 expression posttranscriptionally by increasing the rate of p53 mRNA translation. In this way, N-acetylcysteine induced apoptosis in several transformed cell lines and transformed primary cultures but not in normal cells (Liu et al., 1998). NF-kB induction has been shown to play a role in protecting cells from programmed cell death (see Chapter 9, this volume). HIV-1 infection of primary monocytic cells and myeloid cell lines results in sustained NF-kB activation....

[17 Redox Properties of Vanillyl Alcohol Oxidase

Flavins are a ubiquitous class of redox-active coenzymes that are able to catalyze a number of different chemical reactions when bound to apoproteins. They play an important role in (de)hydrogenation and hydroxylation reactions, in oxygen activation, and in one- and two-electron transfer processes from and to redox centers.1'2 Because of their chemical versatility, flavins are involved in a wide range of biological processes. They have been shown to be involved in programmed cell death by signal transduction3 and in detoxification of a wide variety of aromatic compounds.4 They also have a function in regulating biological clocks,5 in DNA damage repair,6 and plant phototropism.7 These unique properties of flavins are always controlled by specific noncovalent or covalent interactions with the apoproteins to which they are bound.

Are There Other Enzymes Involved in Nitrite Metabolism in Plants

It has long been known that soybean can produce X (NO and NO,) gases from nitrite by the action of the so-called constitutive NRs (Dean and Harper, 1988 Klepper, 1990). Since then, it has been found that many plants have the ability to emit nitrogen oxide(s) (Wildt et al., 1997), a denitrifying capability closely associated with nitrate availability. Interestingly, Goshima et al. (1999) have found emission ofN Oby transgenic tobacco plants expressing an antisense NiR construct (line 271 Vaucheret et al., 1992), which have very low NiR activities and which accumulate nitrite. Emission of N , 0 was not observed in the wild type or in transgenic plants grown on ammonium. Furthermore, when NR activity was blocked, no evolution of N20 was observed (Goshima et al., 1999). Thus, it appears that in tobacco nitrite is partly detoxified by reduction to but whether this step is enzymatic or results from chemical reduction of the nitrite ion remains to be established. Very recently it has also...

Defect In Mitochondrial Oxidative

Current concepts as to the cause of Parkinson's disease suggest an inherited predisposition to environmental or endogenously produced toxic agents causing oxi-dative damage to nigral cells for the following reasons The level of reduced glutathione in substantia nigra is decreased. The depletion of reduced glutathione in the substantia nigra in Parkinson's disease could be the result of neuronal loss. As a matter of fact, a positive correlation has been found to exist between the extent of neuronal loss and depletion of glutathione. A decrease in the availability of reduced glutathione would impair the capacity of neurons to detoxify hydrogen peroxide and increase the risk of free radical formation and lipid peroxidation. Indeed, the nigra contains increased levels of malondialdehyde and hydroperoxides. An increase in the activity of mitochondrial superoxide dismutase in the substantia nigra in Parkinson's disease may indicate a compensatory mechanism to nullify the augmented oxidative...

Molecular Foundations Of Early Pharmacology And Genetics

Applying Bateson's suggestion to exogenous chemicals, Garrod proposed that the noxious effects these substances produce in some persons might be due to failure of their enzymes to detoxify them. In the course of these and later studies, Garrod came to believe that ''substances in foods, drugs and in exhalations of particular animals and plants may produce in some people effects wholly out of proportion to any they bring about in most persons, and that such effects were due to derangement of metabolic factors.'' He also pointed out that ''the ultimate toxic agent could be a product of normal metabolism formed in undue amount, or it could be an intermediate product that escaped the further changes it normally undergoes, or possibly an abnormal product formed by way of derangement of normal metabolic processes,'' and because metabolic deviations from the average were less obvious than variations in form, he believed ''they would attract little attention and the great majority of them...

Normal and Altered Endocrine System Function Normal Endocrine System Function

Four hierarchical levels of endocrine system function include control (hypothalamus and pituitary of the brain), production (gonad), availability (steroid hormone metabolism xenobiotic detoxification and serum binding protein synthesis in the liver), action (receptors in the brain, gonad, and liver). The potential for alteration of steroid hormone concentration exists at each of these levels Fig. 1. Four hierarchical levels of endocrine system function include control (hypothalamus and pituitary of the brain), production (gonad), availability (steroid hormone metabolism xenobiotic detoxification and serum binding protein synthesis in the liver), action (receptors in the brain, gonad, and liver). The potential for alteration of steroid hormone concentration exists at each of these levels

Cancer And Ayurveda An Overview

The Ayurvedic concept of cancer is based on three doshas (body constitutions). The imbalance in doshas (vayu, pitta, and kapha) is the beginning of pathogenesis in the development of cancer.4 The disease is classified according to the dosha vitiated, and the treatment is chosen appropriately to augment the dosha using various procedures, including herbal medications.6 The herbs are classified into groups, depending upon their enhancing or decreasing effect on each dosha. The general cancer healing process include cleansing therapies and treatment with immune-boosting herbs such as Satavari (Asparagus racemosus), Ashwagandha (Withania somniferd), Vidari kand (Puereria tuberosd), etc.6 Ayurveda offers unique therapeutic procedures like pancha karma (five actions) to detoxify the body using several processes, including treatment with herbal concoctions.7 Poorva karma is a pretreatment procedure performed to enhance the immune system.8

Jejunal Transport and Metabolism

Cytochrome P450 (EC enzymes are well known for their ability to metabolize the majority of drugs, to detoxify environmental pollutants, and to activate some classes of carcinogens 93 . The most highly expressed subfamily is CYP 3A, which includes the isoforms CYP 3A4, CYP 3A5, CYP 3A7, and CYP 3A43 93, 94 . The most abundant isoform is CYP 3A4, which corresponds to 30 of the total P450 content in the liver and about 70 of the total P450 content in the

Specific Organosilicon Compounds

Silatranes bearing aryl7,8 and 2-thienyl254 groups at the silicon atom have been shown to be very toxic compounds (LD50 0.3-1.0 mgkg-1). 1-(4-Chloro-phenyl)-silatrane255 has been proposed as a single-dose rodenticide.256 259 It has several distinct features self-detoxification, which minimizes or eliminates the hazard of persistent or long-lasting residues, no secondary poisoning hazard and low dermal toxicity.260

Psychoactive substance use

It seems that prior alcohol and substance abuse are likely risk factors in leading to what is described as a downhill spiral'' in patients with chronic pain involving escalating doses and abuse of opioid therapy. Notwithstanding this, opioid use is not contraindicated in this population, except for those who have evidence of previous drug dependency or who are found to regularly ask for additional medication ahead of schedule. If there is definite evidence of opioid misuse, it is normally advisable to refer the patient to a specialized substance misuse center. Brief psychosocial interventions and contingency management (which consists of payment of money or tokens to patients if they succeed in reducing opiate use) have been found to improve compliance with therapy.75 Drug detoxification may be needed before these strategies are employed the decision rests with the substance misuse team, to whom the patient should be referred if such treatments are being considered.

Treatment Of Alcoholdependence

One pharmacogenetic study analysed the impact of Naltrexone, an antagonist for the mu-opioid receptor, on the reduction of rate of relapse and time to return to heavy drinking in 82 alcohol-dependent patients who successfully completed detoxification from alcohol, compared to 59 controls. The potential impact of this pharmacogenetic approach is particularly rich according to the biological background of alcoholism, as detailed in the neurotransmitter systems involved in alcohol central effects section. Naltrexone blocked the euphoria produced by ethanol (Volpicelli et al., 1995 King et al., 1997). This clinical symptom of feeling high constitutes one of the most frequently quoted factor to explain relapse, and is presented as a way to cope against depressed mood (Strowig, 2000). As an opioid antagonist should block or reduce the effect of alcohol on opioid receptor activity, treated subjects are expected to be less reinforced by alcohol. Indeed, Voplicelli et al., (1995) found that...

Alcohol Dehydrogenase

Alcohol dehydrogenase is much larger than lysozyme. It is an enzyme that can break down alcohol molecules. As such, it is the body's first defense line against alcohol molecules that are toxic for the body and can damage the nervous system. High levels of alcohol dehydrogenase are present in the body to detoxify alcohol. The enzyme does this by converting the alcohol into nontoxic molecules, such as acetate, that are easily used by cells. In this way, a dangerous molecule (alcohol) is converted by alcohol dehydro-genase into harmless foodstuff for the body. The human body has at least nine different types of alcohol dehydrogenase enzymes, each slightly different. Most of these are found in the liver and others in the lining of the stomach. Each enzyme is composed of two chains, and the different dehydrogenases can exchange their chains to create mixed enzymes that are still active. Alcohol is not the only target of these enzymes they also make important modifications to steroids and...

Pharmacotherapy Of Alcoholism

Naltrexone helps to maintain abstinence by reducing the urge to drink and increasing control when a slip occurs. It is not a cure for alcoholism and does not prevent relapse in all patients. Naltrexone works best when used in conjunction with some form of psychosocial therapy, such as cognitive behavioral therapy. It typically is administered after detoxification and given at a dose of 50 mg day for several months. Adherence to the regimen is important to ensure the therapeutic value of naltrexone and has proven to be a problem for some patients. The most common side effect of naltrexone is nausea, which is more common in women than in men and subsides if the patients abstain from alcohol. When given in excessive doses, naltrexone can cause liver damage. It is contraindicated in patients with liver failure or acute hepatitis and should be used only after careful consideration in patients with active liver disease.

Chapter Overview

If lipophilic drugs, or xenobiotics, were not metabolized to polar, readily excretable water-soluble products, they would remain indefinitely in the body, eliciting their biological effects. Thus, the formation of water-soluble metabolites not only enhances drug elimination, but also leads to compounds that are generally pharmacologically inactive and relatively nontoxic. Consequently, drug metabolism reactions have traditionally been regarded as detoxication (or detoxification) processes.1 Unfortunately, it is incorrect to assume that drug metabolism reactions are always detoxifying. Many drugs are biotransformed to pharmacologically active metabolites. These metabolites may have significant


4-aminoazobenzene was carcinogenic in rats, whereas the parent compound 4-aminoazobenzene was very weakly active (Miller and Miller, 1953). Later studies by other investigators have demonstrated that methylation and subsequent oxygenation at nitrogen are necessary to achieve carcinogenicity of a certain type of arylamines. For instance, N-methylation of 4-aminoazobenzene renders it oxidizable by microsomal flavin-containing monooxygenase (Ziegler et al., 1988). Esterification of the resulting AMiydroxylamine then would convert it to an ultimate electro-philic and carcinogenic metabolite. In the case of thiols, methyl transfer mainly represents a detoxification step. In addition to 0-, N-, and S-methylation reactions, direct incorporation of the methyl group to an


Detoxification Detoxification is a process involving the discontinuation or tapering of a substance that an individual has been consuming on a regular basis usually because he she is suffering from an addiction to this substance. Detoxification usually requires medical management and the administration of ancillary medication to ease withdrawal symptoms.

DNA Methylation

Methylation at CpG islands silences transcription. This is one of the common mechanisms for inactivating tumor suppressor genes in tumors. There is evidence to suggest the role of methylation in the outcome to chemotherapy reviewed in (38) . In 70 ovarian cancer patients, methylation status of DNA repair detoxification genes was significantly associated with taxane therapy outcome (p 0.013) (39). Methylation of GGH in acute lymphoblastic leukemia patients was associated with significantly reduced GGH expression (and consequently increased methotrexate polyglutamation) in 34 patients with wild-type germline GGH (40). It is clear that patients without functional polymorphisms in pharmacogenetically relevant genes can still have altered gene expression leading to chemoresistance sensitivity.


The abuse and dependence liability of tramadol was once thought to be quite low. However, several reports have emerged that indicate that tramadol is an agent on which patients may become quite dependent. In one case, a patient had been using such dramatic daily amounts that inpatient methadone detoxification was required (Leo et al. 2000).


Apoptosis by agents that may alter the intracellular redox status, including antioxidants. At present, the exact molecular mechanisms involved in the redox regulation of apoptosis remain elusive. Observational studies show that antioxidants may have antiapoptotic or proapoptotic properties, depending on the type of cells and the apoptosis-inducing signal involved. A trend showing that antioxidants may prevent apoptosis of healthy cells and may promote the apoptosis of diseased cells appears to be emerging. Such an observation, however, is not yet supported by reasonable mechanism-based details. It should be kept in mind that antioxidants may have signal transduction regulatory properties that are independent of their ability to detoxify ROS or to repair oxidative damage. As such, a single line of evidence showing sensitivity to antioxidant treatment should not be interpreted as an indication for the involvement of ROS. A major function of Bcl-2 family proteins is to regulate...


The distribution of GSTs differs both qualitatively and quantitatively from tissue to tissue with the consequence that GSTs in one tissue may influence the levels of circulating substrates important for an effect in another tissue. This has been discussed in relation to tobacco smoke-induced lung cancer in humans, where greater susceptibility to this disease is associated with the null phenotype in a GSTMl polymorphism. This effect may originate in the inability of the livers of individuals with a GSTMl null phenotype to detoxify polycyclic aromatic hydrocarbon diol epoxides, which then enter the circulation to damage the lungs. Occasionally glutathione conjugation results not in detoxication, but the formation of a harder electrophile. This has recently been demonstrated to occur with dichloromethane, which is mutagenic in bacteria (5. typhi-murum TA1535) transfected with a rat GST5 cDNA construct but not with its antisense construct. Since dichloromethane is a commonly used solvent...

Home Detox

Home Detox

Never before revealed. Home Detox - Step By Step Guide To Dextoxify The Body. Has too much late night behavior and partying got you feeling bad about yourself? Are you trying to lose weight but nothing is happening? Maybe you are just sick of all of the toxins that are in the air you breathe, the water you drink and the foods you eat. If so, then you need to do something about it. If you find yourself feeling bad about your health, there are ways that you can help your body right at home.

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