Journal
CLINICAL PHARMACOLOGY & THERAPEUTICS
Volume 85, Issue 3, Pages 312-318Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/clpt.2008.215
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Funding
- Korea Healthcare technology project
- Ministry for Health, Welfare and Family Affairs, Republic of Korea [A080016]
- MOST/KOSEF for the Environmental Biotechnology National Core Research Center [R15-2003-012-02001-0]
- Korea Health Promotion Institute [A080016] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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