4: Common Cytochrome P450 Polymorphisms and Pharmacogenetics

Key Points

• Disease summary:

  • In this chapter, relatively common (>1% frequency) and ethically diverse genetic polymorphisms of drug-metabolizing cytochrome P450s (CYPs) will be reviewed. In general, these variants

  • Affect pharmacokinetics and response to drugs which are substrates of these enzymes

  • Are not usually associated with drug-independent clinical phenotypes

  • Have pharmacokinetic phenotypes categorized as poor, intermediate, normal (extensive), and ultrarapid metabolizer (UM)

  • Have clinical phenotypes which depend on the particular pharmacologic situation (drug, prodrug, therapeutic index, etc)

• Differential diagnosis:

  • Intoxication, drug-drug interaction, allergy

• Monogenic forms:

  • CYP polymorphisms are monogenically inherited as autosomal recessive (poor or intermediate metabolizers) or dominant (UMs) traits.

• Twin studies:

  • The few mono- or dizygotic twin studies available indicate a large contribution of genetic factors to drug oxidation phenotype: heritability of antipyrine 4-hydroxylation rate, which is mainly catalyzed by CYP3A4, was estimated at 0.88 and that of the caffeine metabolic ratio, a marker of CYP1A2, at 0.72.

• Environmental factors:

  • Drug-drug interactions (inhibition, induction), food constituents, circadian rhythm

• Genome-wide associations:

  • GWAS revealed associations between CYP2C9 genotype and final dose of warfarin, an anticoagulant metabolized by the enzyme. Further, single-nucleotide polymorphisms (SNPs) in the regulatory region of the CYP1A locus were associated with habitual coffee consumption; this association is likely based on the major role of CYP1A2 as the rate-limiting enzyme for metabolism of caffeine.

Common Characteristics of Cytochrome P450 Polymorphisms

The influence of heritable genetic polymorphisms in genes encoding drug-metabolizing CYPs on drug pharmacokinetics and drug response is well documented. Clinically relevant polymorphisms exist in CYPs 2B6, 2C9, 2C19, 2D6, and 3A4/5 (see later). In each of these genes, several individual SNPs are found in coding and/or noncoding gene regions, which influence either gene expression or enzymatic activity (Table 4-1). The CYP2D6 gene is also known for its numerous large-scale structural variants including a variety of gene copy number variants (CNV). Variants that lead to lower or higher expression of the enzyme are expected to decrease or increase the clearance of all enzyme substrates in a similar manner, respectively, whereas nonsynonymous coding SNPs may lead to substrate-dependent effects.

Different terms are in use for the associated pharmacokinetic phenotypes. In the case of CYP2D6 and CYP2C19, poor metabolizer (PM) refers to homozygous or compound heterozygous carriers of alleles with a complete lack of function (null allele). An efficient (or extensive) metabolizer (EM) refers to the normal phenotype, usually representing the most common phenotype mode in the population. Intermediate metabolizers (IMs) harbor either one normal or one functionally deficient allele, thus resulting in impaired drug oxidation capacity. Lastly, the UM originates from three or more functional CYP2D6 alleles or from a functionally more active CYP2C19 allele. When referring to other CYPs, these terms are not appropriate because the lack of common null alleles and the functional overlap with enzymes of similar substrate selectivity preclude the ...