Drug Sulfate Conjugation

Adenine

Adenine h203p0

3'-Phosphoadenosine-5'-phosphosulfate (PAPS)

Figure 3.13 • Formation of PAPS and sulfate conjugates.

principal route of metabolism in humans. For many phenols, however, sulfoconjugation may represent only a minor pathway. Glucuronidation of phenols is frequently a competing reaction and may predominate as the conjuga-tive route for some phenolic drugs. In adults, the major urinary metabolite of the analgesic acetaminophen is the O-glucuronide conjugate, with the concomitant O-sulfate conjugate being formed in small amounts.364 Interestingly, infants and young children (ages 3-9 years) exhibit a different urinary excretion pattern: the O-sulfate conjugate is the main urinary product.397,398 The explanation for this reversal stems from the fact that neonates and young children have a decreased glucuronidating capacity because of undeveloped glucuronyltransferases or low levels of these enzymes. Sulfate conjugation, however, is well developed and becomes the main route of acetaminophen conjugation in this pediatric group.

Figure 3.13 • Formation of PAPS and sulfate conjugates.

Sulfate Conjugation Apap

Other functionalities, such as alcohols (e.g., aliphatic C1 to C5 alcohols, diethylene glycol)399,400 and aromatic amines (e.g., aniline, 2-naphthylamine),401,402 can also form sulfate conjugates. These reactions, however, have only minor importance in drug metabolism. The sulfate conjugation of

Sulphate ConjugationStructure Sulphate Conjugation

N-hydroxylamines and N-hydroxylamides takes place as well, occasionally. O-Sulfate ester conjugates of N-hydroxy compounds are of considerable toxicological concern because they can lead to reactive intermediates that are responsible for cellular toxicity. The carcinogenic agents N-methyl-4-aminoazobenzene and 2-AAF are believed to mediate their toxicity through N-hydroxylation to the corresponding N-hydroxy compounds (see earlier section on N-hydroxylation of amines and amides). Sulfoconjugation of the N-hydroxy metabolites yields O-sulfate esters, which presumably are the ultimate carcinogenic species. Loss of SO42" from the foregoing sulfate conjugates generates electrophilic nitrenium species, which may react with nucleophilic groups (e.g., NH2, OH, SH) present in proteins, DNA, and RNA to form covalent linkages that lead to structural and functional alteration of these crucial biomacromolecules.403 The consequences of this are cellular toxicity (tissue necrosis) or alteration of the genetic code, eventually leading to cancer. Some evidence supporting the role of sulfate conjugation in the metabolic activation of N-hydroxy compounds to reactive intermediates comes from the observation that the degree of hepatotoxicity and hepatocarcinogenicity of N-hydroxy-2-acetylaminofluorene depends markedly on the level of sulfo-transferase activity in the liver.404,405

The discontinued analgesic phenacetin is metabolized to N-hydroxyphenacetin and subsequently conjugated with sulfate.406 The O-sulfate conjugate of N-hydroxy-phenacetin binds covalently to microsomal proteins.407

This pathway may represent one route leading to reactive intermediates that are responsible for the hepatotoxicity and nephrotoxicity associated with phenacetin. Other pathways (e.g., arene oxides) leading to reactive electrophilic intermediates are also possible.6

Conjugation with Glycine, Glutamine, and Other Amino Acids

The amino acids glycine and glutamine are used by mammalian systems to conjugate carboxylic acids, particularly aromatic acids and arylalkyl acids.408,409 Glycine conjugation is common to most mammals, whereas glutamine conjugation appears to be confined mainly to humans and other primates. The quantity of amino acid conjugates formed from xenobi-otics is minute because of the limited availability of amino acids in the body and competition with glucuronidation for carboxylic acid substrates. In contrast with glucuronic acid and sulfate, glycine and glutamine are not converted to activated coenzymes. Instead, the carboxylic acid substrate is activated with adenosine triphosphate (ATP) and coenzyme A (CoA) to form an acyl-CoA complex. The latter intermediate, in turn, acylates glycine or glutamine under the influence of specific glycine or glutamine N-acyltransferase enzymes. The activation and acylation steps take place in the mitochondria of liver and kidney cells. The sequence of metabolic events associated with glycine and glutamine conjugation of phenyl-acetic acid is summarized in Figure 3.14. Amino acid conju-

Glycine Chemical Reaction With Drug
Figure 3.14 • Formation of glycine and glutamine conjugates of phenylacetic acid.
Phenylacetic Acid Pathway

gates, being polar and water soluble, are excreted mainly re-nally and, sometimes, in the bile.

Bromphen Dosage

Aromatic acids and arylalkyl acids are the major substrates undergoing glycine conjugation. The conversion of benzoic acid to its glycine conjugate, hippuric acid, is a well-known metabolic reaction in many mammalian systems.410 The extensive metabolism of salicylic acid (75% of dose) to salicyluric acid in humans is another illustrative example.411,412 Carboxylic acid metabolites resulting from oxidation or hydrolysis of many drugs are also susceptible to glycine conjugation. For example, the H1-histamine antagonist bromphen-iramine is oxidized to a propionic acid metabolite that is conjugated with glycine in both human and dog.181 Similarly, p-fluorophenylacetic acid, derived from the metabolism of the antipsychotic agent haloperidol (Haldol), is found as the glycine conjugate in the urine of rats.413 Phenylacetic acid and isonicotinic acid, resulting from the hydrolysis of, respectively, the anticonvulsant phenacemide (Phenurone)414 and the antituberculosis agent isoniazid,415 also are conjugated with glycine to some extent.

Glutamine conjugation occurs mainly with arylacetic acids, including endogenous phenylacetic416 and 3-indolylacetic acid.417 A few glutamine conjugates of drug metabolites have been reported. For example, in humans, the 3,4-dihydroxy-5-methoxyphenylacetic acid metabolite of mescaline is found as a conjugate of glutamine.418 Diphenylmethoxyacetic acid, a metabolite of the antihistamine diphenhydramine (Benadryl), is biotransformed further to the corresponding glutamine derivative in the rhesus monkey.419

Several other amino acids are involved in the conjugation of carboxylic acids, but these reactions occur only occasionally and appear to be highly substrate and species depen-dent.409420 Ornithine (in birds), aspartic acid and serine (in rats), alanine (in mouse and hamster), taurine (H2NCH2CH2SO3H) (in mammals and pigeons), and histi-dine (in African bats) are among these amino acids.420

GSH or Mercapturic Acid Conjugates

GSH conjugation is an important pathway for detoxifying chemically reactive electrophilic compounds.421-428 It is now generally accepted that reactive electrophilic species manifest their toxicity (e.g., tissue necrosis, carcinogenicity, mutagenicity, teratogenicity) by combining covalently with nucleo-philic groups present in vital cellular proteins and nucleic acids.4,429 Many serious drug toxicities may be explained also in terms of covalent interaction of metabolically generated electrophilic intermediates with cellular nucleophiles.5,6 GSH protects vital cellular constituents against chemically reactive species by virtue of its nucleophilic SH group. The SH group reacts with electron-deficient compounds to form S-substi-tuted GSH adducts (Fig. 3.15).421-428

GSH is a tripeptide (y-glutamyl-cysteinylglycine) found in most tissues. Xenobiotics conjugated with GSH usually are not excreted as such, but undergo further biotransformation to give ^-substituted n-acetylcysteine products called mercapturic acids.76,86,424-428 This process involves enzymatic cleavage of two amino acids (namely, glutamic acid and glycine) from the initially formed GSH adduct and subsequent n-acetylation of the remaining ^-substituted cysteine residue. The formation of GSH conjugates and their conversion to mercapturic acid derivatives are outlined in Figure 3.15.

Conjugation of a wide spectrum of substrates with GSH is catalyzed by a family of cytoplasmic enzymes known as GSH ^-transferases.75 These enzymes are found in most tissues, particularly the liver and kidney. Degradation of GSH conjugates to mercapturic acids is carried out principally by renal and hepatic microsomal enzymes (Fig. 3.15).76 Unlike other conjugative phase II reactions, GSH conjugation does not require the initial formation of an activated coenzyme or substrate. The inherent reactivity of the nucleophilic GSH toward an electrophilic substrate usually provides sufficient driving force. The substrates susceptible to GSH conjugation are quite varied and encompass many chemically different classes of compounds. A major prerequisite is that the substrate be sufficiently electrophilic. Compounds that react with GSH do so by two general mechanisms: (a) nucleo-philic displacement at an electron-deficient carbon or heteroatom or (b) nucleophilic addition to an electron-deficient double bond.421-423

Many aliphatic and arylalkyl halides (Cl, Br, I), sulfates (OSO3—), sulfonates (OSO2R), nitrates (NO2), and organophosphates (O-P[OR]2) possess electron-deficient carbon atoms that react with GSH (by aliphatic nucleophilic displacement) to form GSH conjugates, as shown:

gsh"

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  • Ronja
    Why are drugs conjugated with sulphate?
    1 year ago

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