The cytochrome P450 (CYP) genes and pseudogenes are grouped into 18 families and 44 subfamilies according to their sequence similarity. Of these, the CYP1, CYP2 and CYP3 families are particularly important in the metabolism of drugs, collectively accounting for most of their Phase I biotransformation . A recent rare example of participation of a member of another CYP family, CYP4, in the metabolism of a commonly used drug is that of warfarin . Various single nucleotide polymorphisms (SNPs) of CYP enzymes are known to be functionally important and alleles with SNPs in complete disequilibrium are known. For better communication of the results of studies of CYP polymorphisms, what is known as the star nomenclature was suggested [3, 4]. This nomenclature is now almost universally adopted, not only for the CYP genes but also for other genes. The wild-type gene is normally referred to as the *1 allele. For example, the CYP2C19*1 allele refers to the wild-type allele in the CYP2C19 subfamily (http://www.cypalleles.ki.se/).
The enzyme cytochrome P450 2C19 (CYP2C19) participates in the metabolism of a wide array of therapeutic drugs, across many drug classes (Table 1) . The CYP2C19 gene maps onto chromosome 10 (10q24.1-q24.3), and encodes a 490-amino-acid protein. Several polymorphisms of the gene are known to be associated with reduced enzyme activity. Notable among these are CYP2C19*2, characterized by a 681G→A substitution in exon 5 leading to a splice-defective site, and CYP2C19*3, which has a point mutation in exon 4, leading to a premature stop codon. The presence of these alleles is generally considered to be sufficiently predictive for the phenotypes to be inferred from them. Thus individuals homozygous for the CYP2C19*2 and CYP2C19*3 alleles are considered to be poor metabolizers (PM), while subjects with at least one CYP2C19*1 allele are classified as extensive metabolizers (EM). More recent alleles identified include CYP2C19*17-21, few of which have been functionally characterized [6–8]. While the population prevalence of a number of CYP2C19 alleles, and their functional consequences, are well documented [9–11], this is less so for CYP2C19*17. The focus of this critical appraisal is on CYP2C19*17, for which a number of studies have now been reported since its discovery in 2006. Early data suggest that its functional effect may be clinically important. Two specific aims of this study were to summarize data on population prevalence of this allele and to assess critically its functional significance. This is important, as different authors have assigned discordant phenotypes to the CYP2C19*17 homozygotes and heterozygotes. For example, Wang et al. consider those with the CYP2C19*1/*17 heterozygotes as ultrarapid metabolizers (UM), whereas Sugimoto et al. consider them as EMs within the same group as the wild-type CYP2C19*1 homozygotes.
|Drug||Drug class and therapeutic effect|
|Mephenytoin||Anticonvulsant (used as probe drug)|
|Omeprazole||Proton pump inhibitor; antacid|
|Amitriptyline Citalopram Clomipramine||Antidepressant|