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- Title
The CYP3A4*18 Genotype in the Cytochrome P450 3A4 Gene, a Rapid Metabolizer of Sex Steroids, Is Associated With Low Bone Mineral Density.
- Authors
Kang, Y. S.; Park, S. Y.; Yim, C. H.; Kwak, H. S.; Gajendrarao, P.; Krishnamoorthy, N.; Yun, S.-C.; Lee, K. W.; Han, K. O.
- Abstract
Osteoporosis is influenced by genetic factors. The interindividual variability in the activity of CYP3A, the metabolic enzyme of sex hormones, may result from genetic polymorphisms. In a study of 2,178 women of ages 40–79 years, the presence of the CYP3A4*18 variant was found to be significantly associated with low bone mass. In vitro functional analyses indicate that CYP3A4*18 is a gain-of-function mutation in sex steroid metabolism, resulting in rapid oxidation of estrogens and testosterone; in vivo pharmacokinetics using midazolam (MDZ) verify the altered activity of the CYP3A4*18, showing lower metabolic turnover in the mutant than in the wild type. Molecular modeling reveals the structural changes in the substrate recognition sites of CYP3A4*18 that can cause changes in enzymatic activity and that potentially account for the difference between the catalytic activities of estrogen and MDZ, depending on the genotype. The results indicate that a genetic variation in the CYP3A4 gene—as a gain-of-function mutation in the metabolism of certain CYP3A substrates, including sex steroids—may predispose individuals to osteoporosis.Clinical Pharmacology & Therapeutics (2009); 85, 3, 312–318 doi:10.1038/clpt.2008.215
- Subjects
OSTEOPOROSIS genetics; CYTOCHROME P-450; GENETIC polymorphisms; SEX hormones; STEROIDS; BONE density; MIDAZOLAM
- Publication
Clinical Pharmacology & Therapeutics, 2009, Vol 85, Issue 3, p312
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1038/clpt.2008.215