The CYP3A418 Genotype in the Cytochrome P450 3A4 Gene, a Rapid Metabolizer of Sex Steroids, Is Associated With Low Bone Mineral Density

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 ass...

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Published in:Clinical pharmacology and therapeutics 2009-03, Vol.85 (3), p.312-318
Main Authors: Kang, YS, Park, SY, Yim, CH, Kwak, HS, Gajendrarao, P, Krishnamoorthy, N, Yun, S‐C, Lee, KW, Han, KO
Format: Article
Language:English
Subjects:
Adult
Aged
Biological and medical sciences
Bone Density - genetics
Cytochrome P-450 CYP3A - genetics
Cytochrome P-450 CYP3A - physiology
Female
Genetic Variation - genetics
Genotype
Gonadal Steroid Hormones - genetics
Gonadal Steroid Hormones - metabolism
Humans
Medical sciences
Middle Aged
Mutation
Osteoporosis - enzymology
Osteoporosis - genetics
Osteoporosis - metabolism
Pharmacology. Drug treatments
Polymorphism, Genetic - genetics
Protein Conformation
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Summary: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
ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2008.215