Abstract
The CYP3A4 enzyme is the most abundant human cytochrome P450 (CYP) and is regarded as the most important enzyme involved in drug metabolism. Inter-individual and inter-population variability in gene expression and enzyme activity are thought to be influenced, in part, by genetic variation. Although Southern African individuals have been shown to exhibit the highest levels of genetic diversity, they have been under-represented in pharmacogenetic research to date. Therefore, the aim of this study was to identify genetic variation within CYP3A4 in three South African population groups comprising of 29 Khoisan, 65 Xhosa and 65 Mixed Ancestry (MA) individuals. To identify known and novel CYP3A4 variants, 15 individuals were randomly selected from each of the population groups for bi-directional Sanger sequencing of ~600 bp of the 5′-upstream region and all thirteen exons including flanking intronic regions. Genetic variants detected were genotyped in the rest of the cohort. In total, 24 SNPs were detected, including CYP3A4*12, CYP3A4*15, and the reportedly functional CYP3A4*1B promoter polymorphism, as well as two novel non-synonymous variants. These putatively functional variants, p.R162W and p.Q200H, were present in two of the three populations and all three populations, respectively, and in silico analysis predicted that the former would damage the protein product. Furthermore, the three populations were shown to exhibit distinct genetic profiles. These results confirm that South African populations show unique patterns of variation in the genes encoding xenobiotic metabolizing enzymes. This research suggests that population-specific genetic profiles for CYP3A4 and other drug metabolizing genes would be essential to make full use of pharmacogenetics in Southern Africa. Further investigation is needed to determine if the identified genetic variants influence CYP3A4 metabolism phenotype in these populations.
Highlights
The human CYP3A enzymes are regarded as the most prominent Cytochrome P450 (CYP) subfamily in facilitating the elimination of drugs, other xenobiotic compounds and endogenous molecules from the body (Lamba et al, 2002)
The previously described alleles CYP3A4∗1B and ∗1G were present in all three populations, while CYP3A4∗12 and CYP3A4∗15 were only present in the Xhosa population
CYP3A4∗24 was present in all three population groups, while CYP3A4∗23 was present in the Xhosa and Khoisan populations
Summary
The human CYP3A enzymes are regarded as the most prominent Cytochrome P450 (CYP) subfamily in facilitating the elimination of drugs, other xenobiotic compounds and endogenous molecules from the body (Lamba et al, 2002). The pharmacogenetically relevant CYP3A4 is responsible for metabolizing 50–60% of all clinically prescribed drugs (Guengerich, 1999) and is listed among The Pharmacogenetics and Pharmacogenomics Knowledge Base’s (PharmGKB’s) “very important pharmacogenes” (http://www.pharmgkb.org/gene/ PA130?tabType=tabVip). The enzyme is predominantly expressed in the liver and small intestine (Shimada and Guengerich, 1989). Expression has as much as 40-fold variation between individual human livers and a 10-fold variation in the metabolism of CYP3A4 substrates in vivo (Shimada and Guengerich, 1989; Lown et al, 1995; Guengerich, 1999). While complex regulatory pathways and environmental factors are important, it is suspected that a portion of this inter-individual variation can be attributed to genetic variants located within the coding gene regions as well as its core regulatory regions, which affect either the expression level or the functional protein of the gene (Steimer and Potter, 2002; Lamba et al, 2002)
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