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The genetic determinants of the CYP3A5 polymorphism
Abstract
CYP3A proteins comprise a significant portion of the hepatic cytochrome P450 (CYP) protein and they metabolize around 50% of drugs currently in use. The dissection of the individual contributions of the four CYP3A genes identified in humans to overall hepatic CYP3A activity has been hampered by sequence and functional similarities. We have investigated the expression of CYP3A5 and its genetic determinants in a panel of 183 Caucasian liver samples. CYP3A5 expression is increased in 10% of livers in this ethnic group. Using a high density map of CYP3A5 variants, we searched for genetic markers of the increased CYP3A5 expression. In agreement with an independent, recent study, we report that a SNP within intron 3 (g.6986G>A) is the primary cause of the CYP3A5 protein polymorphism. The frequencies of the g.6986A variant which allow for normal splicing of CYP3A5 transcripts are 5% in Caucasians, 29% in Japanese, 27% in Chinese, 30% in Koreans and 73% in African-Americans. In the last ethnic group, the expression of CYP3A5 in some individuals who carry the g.6986A variant is affected adversely by a frame shift mutation (CYP3A5*7, D348., q = 0.10). In summary, these results should add to efforts to identify clinically relevant, CYP3A5-specific reactions and to further elucidate traits responsible for variable expression of the entire CYP3A family.
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Citations
Cited by
Zanger, U. M., & Schwab, M. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.12.007 · Cited by 4,169
Self-citationGenetic contribution to variable human CYP3A-mediated metabolism
Lamba, J. K., Lin, Y. S., Schuetz, E. G., & Thummel, K. E. (2002) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(02)00066-2 · Cited by 990
Clinical Pharmacokinetics and Pharmacodynamics of Tacrolimus in Solid Organ Transplantation
Staatz, C. E., & Tett, S. E. (2004) · Clinical Pharmacokinetics · doi:10.2165/00003088-200443100-00001 · Cited by 913
Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation
Zanger, U. M., Turpeinen, M., Klein, K., & Schwab, M. (2008) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-008-2291-6 · Cited by 593
Self-citationHaufroid, V., Mourad, M., Van Kerckhove, V., Wawrzyniak, J., De Meyer, M., Eddour, D. C., Malaise, J., Lison, D., Squifflet, J.-P., & Wallemacq, P. (2004) · Pharmacogenetics · doi:10.1097/00008571-200403000-00002 · Cited by 447
Metadata
- Authors
- Hustert, E., Haberl, M., Burk, O., Wolbold, R., He, Y.-Q., Klein, K., Nuessler, A. C., Neuhaus, P., Klattig, J., Eiselt, R., Koch, I., Zibat, A., Brockmöller, J., Halpert, J. R., Zanger, U. M., & Wojnowski, L.
- Venue
- Pharmacogenetics
- Published
- 2001-12
- Volume
- 11
- Issue
- 9
- Pages
- 773-779
- ISSN
- 0960-314X (ISSN-L)
- OpenAlex
- W2358501499
- Cited by
- 673
- References
- 0
- FWCI
- 20.76
- Type
- journal article
- Language
- en
- Open access
- closed
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- Hustert, E., Haberl, M., Burk, O., Wolbold, R., He, Y.-Q., Klein, K., Nuessler, A. C., Neuhaus, P., Klattig, J., Eiselt, R., Koch, I., Zibat, A., Brockmöller, J., Halpert, J. R., Zanger, U. M., & Wojnowski, L. (2001). The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics. https://doi.org/10.1097/00008571-200112000-00005
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