Genetic contribution to variable human CYP3A-mediated metabolism
Section snippets
Multiplicity of CYP3A enzymes
The human CYP3A subfamily, CYP3A4, CYP3A5, CYP3A7 and CYP3A43, is one of the most versatile of the biotransformation systems that facilitate the elimination of drugs, other xenobiotic compounds, and endogenous molecules from the body. Although there has been no systematic analysis of the extent of its contribution, it is generally accepted that CYP3A enzymes play a dominant role in the metabolic elimination of more drugs than any other biotransformation enzyme. CYP3A metabolic versatility may
CYP3A4 genetic variation
Unlike other human P450s (e.g., CYP2D6, CYP2C19), there is no evidence of a ‘null’ allele for CYP3A4. Genetic variation found in the flanking, intronic and exonic regions of the gene may influence the level or function of CYP3A4 protein, but full length mRNA has been detected in all adults studied to date.
CYP3A5 genetic variation
The CYP3A5 cDNA sequence was first described independently by Aoyama et al. [23] and Schuetz et al. [85]. The allele corresponding to this cDNA and the respective expressed protein was designated wild-type, CYP3A5*1A. Subsequent work described 5′-flanking sequence of two distinctly different genomic clones from a human liver containing CYP3A5 protein [86]. The clones contained identical sequences for exon 1 but differed slightly in the 5′-flanking sequence. The flanking sequence corresponding
Mutations in CYP3A7 5′-flanking, coding and intronic domains
The identification of SNPs in the CYP3A7 gene has lagged somewhat behind research on CYP3A4 and CYP3A5. Compared to the wild-type sequence (CYP3A7*1A [106]), Kuehl et al. [17] identified four unique mutations in the CYP3A7 5′-flanking region. Three of the mutations represent SNPs (CYP3A7*1B, *1D and *1E) and occurred in regions outside of those associated with the regulation of CYP3A transcription. The fourth mutation (CYP3A7*1C) consists of the replacement of 60 bp from the CYP3A4 gene with
CYP3A43 splicing variation
One of the most interesting aspects of the CYP3A43 research to emerge is the apparent propensity for alternative splicing events. Sequence analysis of different cDNA isolated from human liver indicated exon skipping and complete or partial intron exclusion [11]. Subsequent work from the same research group demonstrated the formation of CYP3A43–CYP3A4 mRNA hybrids [110]. Some of these CYP3A43 hybrids (exon 1 of CYP3A43 joined to exons 2–13 of CYP3A4) retained catalytic activity, although the
Summary
Numerous different mutations in the CYP3A genes have been identified. The most significant of these mutations are found in CYP3A5 and CYP3A7. For CYP3A5, a SNP within intron-3 (CYP3A5*3) results in aberrant mRNA splicing and a pronounced reduction in protein synthesis. Depending on ethnicity, the wild-type CYP3A5*1 allele frequency varies between 5 and 45%. Livers and small intestines that have at least one CYP3A5*1 allele exhibit, on average, increased metabolic clearance of midazolam,
Acknowledgements
This work was supported in part by grants from the National Institutes of Health (GM07750, GM63666, ES07033, GM32165, GM60346, GM61393, ES08658, P30 CA21765 and CA51001); and by the American Lebanese Syrian Associated Charities.
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