CYP450 System

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The cytochromes are a family of proteins (enzymes) that play a key role in the oxidative metabolism of drugs (e.g., ^-blockers, antihypertensives, antiarrhythmics, monoamine oxidase inhibitors, and so on). Approximately 70% of the human liver CYPs are accounted for by CYP1A2, CYP2A6, CYP2B6, CYP2C, CYP2D6, CYP2E1, and CYP3A (136). CYP2D6 is of particular clinical importance both because a number of commonly prescribed drugs are substrates of this enzyme and also due to interindividual and ethnic differences in its ability to perform its role in drug metabolism. In addition, CYP2D6 polymorphism has been extensively studied and associated with metabolism of debrisoquine and sparteine. The CYP2D6 gene on chromosome 22 that encodes this enzyme is highly polymorphic and more than 50 allelic variants have been identified, although many of these occur in a very small number of individuals. Although most of these variants are polymorphic, these do not have any direct effect on the expression or activity of the enzyme they encode. Nonetheless, these variants partition the population into three phenotypes in terms of their ability to metabolize drugs to either active or inactive metabolites: extensive metabolizers (EM), poor metabolizers (PM), and ultrarapid meta-bolizers (URM), as shown in Figure 3. Individuals capable of efficient drug metabolism are termed EM, whereas individuals with a deficiency in metabolism, typically resulting from the mutation or deletion of both alleles of the gene, are termed PM. Conversely, over-expression due to CYP2D6 gene amplification results in URM. The prevalence of genetic variants and their clinical impact varies substantially in the three groups across all racial and population groups. For example, approximately 5% to 10% of the Caucasians and 2% to 3% of the black Americans, and 1% of the Asians are PMs of CYP2D6 (137,138).

From the alleles identified, CYP2D6*4 is the most common allele among PMs. This allele is associated with a splice site mutation and as a consequence does not produce a functional enzyme (139). In addition, the CYP2D6* 3 allele, which contains a frame-shift mutation, also produces a PM phenotype. The CYP2D*5 allele, which is a complete gene mutation, also produces this PM phenotype. The earliest evidence for polymorphic expression of CYP2D6 was observed in the clinical trials of antihypertensive treatment debrisoquine. Liver biopsy studies established that those patients who were PMs of deb-risoquine had a deficiency in CYP450 mono-oxygenase activity resulting from ineffective binding of substrate to the enzyme (140). Because the CYP2D6 polymorphisms are recessive traits, the heterozygous individuals with one active and one mutant allele manifest metabolism of the substrate, which does not differ overtly from a person of normal phe-notype. However, these heterozygous individuals may display a slightly increased metabolic rate that points to a deficiency of, or a reduction in, metabolic capacity. These

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Increasing metabolic capacity

Figure 3 Cytochrome P450 enzyme showing polymorphic distribution. Abbreviations: PM, poor metabolizers; EM, extensive metabolizers; URM, ultra rapid metabolizers.

individuals are the EMs and represent the great majority of the population. URMs, on the other hand, occur as a result of the duplication of the CYP2D6*2 allele. The enzyme produced by the CYP2D6*2 allele is similar to that produced by the CYP2D6*1 allele. However, certain individuals may inherit 2, 3, 4, 5, or as many as 13 gene copies arranged in tandem and thus produce proportionally higher amounts of the enzyme (141). The other SNPs detected are numbered as indicated in the standardized CYP2D6 nomenclature (142).

As mentioned previously, a number of drugs are metabolized by these enzymes, and it is possible that the CYP2D6-related genotype interacts with target polymorphisms (e.g., beta-adrenergic receptor polymorphisms) and polymorphisms in genes involved in cardiovascular pathophysiology (e.g., ACE I/D polymorphism) to influence overall response to beta-blockers. One study found that the clearance of the R(+) enantiomer of carvedilol was 66% lower, and the area under the concentration-versus-time curve was 156% higher among PMs than EMs (143). CYP2D6 allelic variants also associated with adverse drug reactions through various mechanisms (see the chapter on adverse drug reactions) (144,145). CYP2D6 PMs manifest reduced clearance of the antianginal drug perhexilene, which accumulates in such organs as liver and nerves, causing hepatotoxicity and peripheral neuropathy (146). Although tremendous progress has been made in elucidating the molecular basis of variation in P450 enzyme expression and activity, the adverse effect in PMs probably represents the greatest impact of CYP2D6 polymorphic variant observed in clinical practice.

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