Abstract
The cytochrome P450 (CYP) enzymes are major players in drug metabolism. More than 2,000 mutations have been described, and certain single nucleotide polymorphisms (SNPs) have been shown to have a large impact on CYP activity. Therefore, CYPs play an important role in inter-individual drug response and their genetic variability should be factored into personalized medicine. To identify the most relevant polymorphisms in human CYPs, a text mining approach was used. We investigated their frequencies in different ethnic groups, the number of drugs that are metabolized by each CYP, the impact of CYP SNPs, as well as CYP expression patterns in different tissues. The most important polymorphic CYPs were found to be 1A2, 2D6, 2C9 and 2C19. Thirty-four common allele variants in Caucasians led to altered enzyme activity. To compare the relevant Caucasian SNPs with those of other ethnicities a search in 1,000 individual genomes was undertaken. We found 199 non-synonymous SNPs with frequencies over one percent in the 1,000 genomes, many of them not described so far. With knowledge of frequent mutations and their impact on CYP activities, it may be possible to predict patient response to certain drugs, as well as adverse side effects. With improved availability of genotyping, our data may provide a resource for an understanding of the effects of specific SNPs in CYPs, enabling the selection of a more personalized treatment regimen.
Highlights
Inter-individual variability of drug response and drug clearance is a complex and common problem in clinical practice [1]
single nucleotide polymorphisms (SNPs) predominantly occurred in 3 polymorphic cytochrome P450 (CYP) (2D6, 2A6 and 2B6) regardless of ethnic group
Compared to the “Human Cytochrome P450 Allele Nomenclature Database”, we found several SNPs in 1,000 Genomes not related to alleles defined and named in the Database
Summary
Inter-individual variability of drug response and drug clearance is a complex and common problem in clinical practice [1]. SNPs in phase 1 enzymes, such as cytochrome P450 oxidases (CYPs) [3], phase 2 enzymes, such as Uridine 5'-diphosphoglucuronosyltransferase (UGTs) [5], and absorptive and efflux transporters, such as ATP-binding cassette transporters (ABCtransporters) [4], have been previously reported. Characterization of these enzymes and the effects of minor allele variants on the metabolism of specific drugs have been described in the literature and have recently been compiled by our group into a comprehensive database called SuperCYP [6]. Using oxygen and NADPH as a co-substrate, CYPs are the major enzymes responsible for catalyzing such reactions [7] and account for approximately 75% of total drug metabolism [8]
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