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The CYP3A4*18 Genotype in the Cytochrome P450 3A4 Gene, a Rapid Metabolizer of Sex Steroids, Is Associated With Low Bone Mineral Density
Author(s) -
Kang YS,
Park SY,
Yim CH,
Kwak HS,
Gajendrarao P,
Krishnamoorthy N,
Yun SC,
Lee KW,
Han KO
Publication year - 2009
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2008.215
Subject(s) - cyp3a4 , cyp3a , genotype , bone remodeling , cytochrome p450 , endocrinology , medicine , bone mineral , biology , osteoporosis , pharmacokinetics , cyp2d6 , pharmacology , chemistry , metabolism , genetics , gene
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