Significance of the Minor Cytochrome P450 3A Isoforms
- 1 January 2006
- journal article
- review article
- Published by Springer Science and Business Media LLC in Clinical Pharmacokinetics
- Vol. 45 (1), 13-31
- https://doi.org/10.2165/00003088-200645010-00002
Abstract
Cytochrome P450 (CYP) 3A4 is responsible for most CYP3A-mediated drug metabolism but the minor isoforms CYP3A5, CYP3A7 and CYP3A43 also contribute. CYP3A5 is the best studied of the minor CYP3A isoforms. It is well established that only approximately 20% of livers express CYP3A5. The most common reason for the absence of expression is a splice site mutation. The frequency of variant alleles shows interethnic differences, with the wild-type CYP3A5* allele more common in Africans than Caucasians and Asians. In individuals who express CYP3A5, the percentage contributed to total hepatic CYP3A by this isoform is still unclear, with estimates ranging from 17% to 50%. CYP3A5 is also expressed in a range of extrahepatic tissues. Only limited information is available on the regulation of CYP3A5 expression but it appears to be inducible via the glucocorticoid receptor, pregnane X receptor and constitutive androstane receptor-β, as for CYP3A4. Although information on the substrate specificity of CYP3A5 is limited compared with CYP3A4, there have been a number of recent pharmacokinetic studies on a small range of substrates in individuals of known genotype to investigate the contribution of CYP3A5. In the case of midazolam, Ciclosporin, nifedipine and docetaxel, clearance by individuals with a CYP3A5-expressing genotype did not differ from that for nonexpressors, but in the case of tacrolimus, eight independent studies have demonstrated faster clearance by those carrying one or two CYP3A5*1 alleles. This may reflect faster turnover of tacrolimus by CYP3A5 than the other substrates. CYP3A5 genotype may affect cancer susceptibility. Certain combined CYP3A4/CYP3A5 haplotypes show differential susceptibility to prostate cancer and there is a nonsignificant increase in the risk of small-cell lung cancer for a CYP3A5* 1/*1 genotype. Females positive for CYP3A5*1 appear to reach puberty earlier, which may affect breast cancer risk. CYP3A5*1 homozygotes may have higher systolic blood pressure. CYP3A7 is predominantly expressed in fetal liver but is also found in some adult livers and extrahepatically. The molecular basis for expression in adult liver relates to upstream polymorphisms, which appear to increase homology to CYP3A4 and make regulation of expression more similar. CYP3A7 has a specific role in hydroxylation of retinoic acid and 16α-hydroxylation of steroids, and is therefore of relevance both to normal development and carcinogenesis. CYP3A43 is the most recently discovered CYP3A isoform. In addition to a low level of expression in liver, it is expressed in prostate and testis. Its substrate specificity is currently unclear. Polymorphisms predicting absence of active enzyme have been identified.Keywords
This publication has 116 references indexed in Scilit:
- Expression and induction of CYP3As in human fetal hepatocytesBiochemical and Biophysical Research Communications, 2004
- First report of a genetic polymorphism of the cytochrome P450 3A43 (CYP3A43) gene: Identification of a loss-of-function variantHuman Mutation, 2003
- Cooperative Regulation of CYP3A5 Gene Transcription by NF-Y and Sp Family MembersBiochemical and Biophysical Research Communications, 2001
- Cloning and Tissue Distribution of a Novel Human Cytochrome P450 of the CYP3A Subfamily, CYP3A43Biochemical and Biophysical Research Communications, 2001
- Functionally Conserved Xenobiotic Responsive Enhancer in Cytochrome P450 3A7Biochemical and Biophysical Research Communications, 2001
- Evidence for the Presence of a Functional Pregnane X Receptor Response Element in the CYP3A7 Promoter GeneBiochemical and Biophysical Research Communications, 1999
- Interindividual Differences in Hepatic Expression of CYP3A4: Relationship to Genetic Polymorphism in the 5′-Upstream Regulatory RegionBiochemical and Biophysical Research Communications, 1999
- The Fetal Specific GeneCYP3A7Is Inducible by Rifampicin in Adult Human Hepatocytes in Primary CultureBiochemical and Biophysical Research Communications, 1996
- P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclaturePharmacogenetics, 1996
- Sequence of the 5′-Flanking Region of CYP3A5: Comparative Analysis with CYP3A4 and CYP3A7Biochemical and Biophysical Research Communications, 1994