As described in Chapter 4, biotransformation reactions mediated by P450 phase I enzymes typically modify functional groups (−OH, −SH, −NH2, −OCH3) of endogenous and xenobiotic compounds, resulting in an alteration of the biological activity of the compound. Phase I enzymes are involved in the biotransformation of over 75% of prescription drugs; therefore, polymorphisms in these enzymes may significantly affect blood levels, which in turn may alter response to many drugs. Polymorphisms in drug-metabolizing enzymes dominated the field of pharmacogenomics for many years, and for some years, metabolic phenotypes such as extensive metabolizer (EM), reflecting an individual’s metabolic rate of a particular drug that is a known substrate of a specific enzyme, were used to describe genetic effects on drug metabolism. After genotypic information became available, a new nomenclature was used to characterize an individual’s metabolic rate. In particular, diplotypes, consisting of one maternal and one paternal allele, using star (*) allele nomenclature, have been used. Each star (*) allele is defined by specific sequence variation(s) within the gene locus, eg, single nucleotide polymorphisms (SNPs), and may be assigned a functional activity score when the functional characterization is known, eg, 0 for nonfunctional, 0.5 for reduced function, and 1.0 for fully functional. Some genes, such as CYP2D6, are subject to whole gene deletions, eg, CYP2D6*5, and whole gene duplications or multiplications, eg, *1xN, *2xN, where N is the number of copies. If more than one copy of the gene is detected, the activity score is then multiplied by the number of copies observed. Enzyme activity is generally a co-dominant or additive trait. For example, if an individual carries one normal function allele and one nonfunctional allele, he will have an intermediate metabolic activity or be considered an intermediate metabolizer (IM). The sum of allelic activity scores typically ranges between 0 and ≥ 3.0 and is most often used to define phenotypes as follows: 0 = PM (poor metabolizer), 0.5 = IM, 1.0–2.0 = EM, and ≥ 2.0 = UM (ultra-rapid metabolizer).
As described in Chapter 4, cytochrome P450 2D6 is involved in the metabolism of up to one quarter of all drugs used clinically, including predominantly basic compounds such as β blockers, antidepressants, antipsychotics, and opioid analgesics. Among the CYP enzymes, CYP2D6 is responsible for metabolism of about 20% of clinically used drugs. Similar to other polymorphic enzymes, four clinically defined metabolic phenotypes, ie, PMs, IMs, EMs, and UMs, are used to predict therapeutic and adverse responses following the administration of CYP2D6 substrates.
The gene encoding CYP2D6 is highly polymorphic, with over 100 alleles defined (www.cypalleles.ki.se/cyp2d6.htm); however, greater than 95% of phenotypes can be accounted for with just nine alleles, ie, CYP2D6 alleles *3, *4, *5, and *6 are nonfunctional; alleles *10, *17, and *41 have reduced function; and alleles *1 and *2 are fully functional. As with many polymorphisms, allele frequencies vary across populations (Table 5–1). Some genetic variants are shared among populations at similar allele frequencies, whereas others vary considerably. For example, the most common nonfunctional allele, CYP2D6*4, is observed at
TABLE 5–1 Major alleles and frequencies in African, Asian, and European populations.