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44 SECTION I General Principles Table 3-1

Xenobiotic Metabolizing Enzymes

Enzymes

Phase 1 "oxygenases"

Cytochrome P450s (P450 or CYP) Flavin-containing monooxygenases (FMO) Epoxide hydrolases (mEH, sEH)

Phase 2 "transferases" Sulfotransferases (SULT) UDP-glucuronosyltransferases (UGT) Glutathione-S-transferases (GST) N-acetyltransferases (NAT) Methyltransferases (MT)

Other enzymes

Alcohol dehydrogenases Aldehyde dehydrogenases NADPH-quinone oxidoreductase (NQO)

Reactions

C and O oxidation, dealkylation, others N, S, and P oxidation Hydrolysis of epoxides

Addition of sulfate Addition of glucuronic acid Addition of glutathione Addition of acetyl group Addition of methyl group

Reduction of alcohols Reduction of aldehydes Reduction of quinones mEH and sEH are microsomal and soluble epoxide hydrolase. UDP, uridine diphosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate.

The phase 1 CYPs, FMOs, and EHs, and some phase 2 conjugating enzymes, notably the UGTs, are located in the endoplasmic reticulum (ER) of the cell (Figure 3-1). The ER lumen is physically distinct from the rest of the cytosolic components and is ideally suited for the metabolic function of these enzymes: hydrophobic molecules enter the cell and embed in the lipid bilayer, where they encounter the phase 1 enzymes. Once oxidized, drugs are conjugated in the membrane by the UGTs

FIGURE 3-1 Location of CYPs in the cell. The figure shows increasingly microscopic levels of detail, sequentially expanding the areas within the black boxes. CYPs are embedded in the phospholipid bilayer of the endoplasmic reticulum (ER). Most of the enzyme is located on the cytoplasmic surface of the ER. A second enzyme, NADPH-cytochrome P450 oxidoreductase, transfers electrons to the CYP where it can, in the presence of O2, oxidize xenobiotic substrates, many of which are hydrophobic and dissolved in the ER. A single NADPH-CYP oxidoreductase species transfers electrons to all CYP isoforms in the ER. Each CYP contains a molecule of iron-protoporphyrin IX that functions to bind and activate O2. Substituents on the porphyrin ring are methyl (M), propionyl (P), and vinyl (V) groups.

FIGURE 3-1 Location of CYPs in the cell. The figure shows increasingly microscopic levels of detail, sequentially expanding the areas within the black boxes. CYPs are embedded in the phospholipid bilayer of the endoplasmic reticulum (ER). Most of the enzyme is located on the cytoplasmic surface of the ER. A second enzyme, NADPH-cytochrome P450 oxidoreductase, transfers electrons to the CYP where it can, in the presence of O2, oxidize xenobiotic substrates, many of which are hydrophobic and dissolved in the ER. A single NADPH-CYP oxidoreductase species transfers electrons to all CYP isoforms in the ER. Each CYP contains a molecule of iron-protoporphyrin IX that functions to bind and activate O2. Substituents on the porphyrin ring are methyl (M), propionyl (P), and vinyl (V) groups.

or by the cytosolic transferases such as GST and SULT. The metabolites are then transported out of the cell and into the bloodstream. Hepatocytes, which constitute >90% of the cells in the liver, carry out most drug metabolism and produce conjugated substrates that can also be transported though the bile canalicular membrane into the bile for elimination in the gut (see Chapter 2).

THE CYPs CYPs are heme proteins (Figure 3-1). The heme iron binds oxygen in the CYP active site, where oxidation of substrates occurs. Electrons are supplied by the enzyme NADPH-cytochrome P450 oxidoreductase and its cofactor, NADPH. Metabolism of a substrate by a CYP consumes one molecule of O2 and produces an oxidized substrate and a molecule of water. Depending on the nature of the substrate, the reaction for some CYPs is partially "uncoupled," consuming more O2 than substrate metabolized and producing "activated oxygen" or O2-. The O2- is usually converted to water by the enzyme superoxide dismutase.

Among the diverse reactions carried out by mammalian CYPs are N-dealkylation, O-dealkylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, and dehalogenation (Table 3-2). CYPs are involved in the metabolism of dietary and xenobiotic agents, as well as the synthesis of endogenous compounds that are derived from cholesterol (e.g., steroid hormones and bile acids).

The CYPs that carry out xenobiotic metabolism have the capacity to metabolize a large number of structurally diverse chemicals. This is due both to multiple forms of CYPs and to the capacity of a single CYP to metabolize structurally dissimilar chemicals. A single compound can be metabolized by multiple CYPs and CYPs can metabolize a single compound at multiple positions. This promiscuity of CYPs (Table 3-2), due to their large and fluid substrate binding sites, occurs at the cost of relatively slow catalytic rates. Eukaryotic CYPs metabolize substrates at a fraction of the rate of more typical enzymes involved in intermediary metabolism and mitochondrial electron transfer. As a result, drugs generally have half-lives in the range of 3-30 hours, while endogenous compounds have half-lives of seconds to minutes.

The broad substrate specificity of CYPs is one of the underlying reasons for the high frequency of drug interactions. When two coadministered drugs are both metabolized by a single CYP, they compete for binding to the enzyme's active site. This can result in the inhibition of metabolism of one or both of the drugs, leading to elevated plasma levels. For drugs with a narrow therapeutic index, the elevated serum levels may elicit unwanted toxicities. Drug-drug interactions are among the leading causes of adverse drug reactions.

THE NAMING OF CYPs

There are 57 functional CYP genes and 58pseudogenes in humans. These genes are grouped into families and subfamilies. CYPs are named with the root "CYP" followed by a number designating the family, a letter denoting the subfamily, and a second number designating the CYP isoform. Thus, CYP3A4 is family 3, subfamily A, and gene number 4. In humans, 12 CYPs in families 1—3 (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5) are primarily responsible for xenobiotic metabolism. The liver contains the greatest abundance of xenobiotic-metabolizing CYPs; CYPs also are expressed throughout the GI tract, and, in lower amounts, in lung, kidney, and the central nervous system (CNS). The most important CYPs for drug metabolism are those in the CYP2C, CYP2D, and CYP3A subfamilies. CYP3A4—the most abundantly expressed—is involved in the metabolism of ~50% of clinically used drugs (Figure 3—2A). The CYP1A, CYP1B, CYP2A, CYP2B, and CYP2E subfamilies are rarely involved in the metabolism of therapeutic drugs, but they catalyze the metabolic activation of many protoxins and procarcinogens.

There are large interindividual variations in CYP activity due to genetic polymorphisms and differences in gene regulation (see below). Several human CYP genes exhibit polymorphisms, including CYP2A6, CYP2C9, CYP2C19, and CYP2D6.

DRUG-DRUG INTERACTIONS Interactions at the level of drug metabolism form the basis of many drug interactions. Most commonly, an interaction occurs when two drugs (e.g., a statin and a macrolide antibiotic or antifungal) are metabolized by the same enzyme and affect each other's metabolism. Thus, it is important to determine the identity of the CYP that metabolizes a particular drug and to avoid coadministering drugs that are metabolized by the same CYP. Some drugs can also inhibit CYPs independently of being substrates. For example, the common antifungal agent, keto-conazole (Nizoral) is a potent inhibitor of CYP3A4 and other CYPs. Coadministration of ketocona-zole with the anti-HIV viral protease inhibitors reduces the clearance of the protease inhibitor and increases its plasma concentration and the risk of toxicity. For most drugs, the package insert lists the CYP that carries out its metabolism and notes the potential for drug interactions. Some drugs are CYP inducers that can induce not only their own metabolism but also the metabolism of coadministered

Major Reactions Involved in Drug Metabolism

Reaction

Examples

I. Oxidative reactions N-Dealkylation

O-Dealkylation

Aliphatic hydroxylation

Aromatic hydroxylation

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