title: The CYP3A4*18 genotype in the cytochrome P450 3A4 gene, a rapid metabolizer of sex steroids, is associated with low bone mineral density.
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.
authors.affiliation: Department of Internal Medicine, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, Korea.
authors.forename: Y S
authors.initials: YS
authors.lastname: Kang
authors.forename: S Y
authors.initials: SY
authors.lastname: Park
authors.forename: C H
authors.initials: CH
authors.lastname: Yim
authors.forename: H S
authors.initials: HS
authors.lastname: Kwak
authors.forename: P
authors.initials: P
authors.lastname: Gajendrarao
authors.forename: N
authors.initials: N
authors.lastname: Krishnamoorthy
authors.forename: S-C
authors.initials: SC
authors.lastname: Yun
authors.forename: K W
authors.initials: KW
authors.lastname: Lee
authors.forename: K O
authors.initials: KO
authors.lastname: Han
mesh_terms: D000328:Adult; D000368:Aged; D015519:Bone Density / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000502:physiology; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D012739:Gonadal Steroid Hormones / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010024:Osteoporosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D011487:Protein Conformation
chemical_list: D012739:Gonadal Steroid Hormones; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human