The CYP3A4*18 genotype in the cytochrome P450 3A4 gene, a rapid metabolizer of sex steroids, is associated with low bone mineral density

Y. S. Kang, S. Y. Park, C. H. Yim, H. S. Kwak, P. Gajendrarao, Navaneethakrishnan Krishnamoorthy, S. C. Yun, K. W. Lee, K. O. Han

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)312-318
Number of pages7
JournalClinical Pharmacology and Therapeutics
Volume85
Issue number3
DOIs
Publication statusPublished - 1 Mar 2009
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP3A
Bone Density
Steroids
Genotype
Genes
Midazolam
Osteoporosis
Estrogens
Mutation
Gonadal Steroid Hormones
Genetic Polymorphisms
Testosterone
Pharmacokinetics
Bone and Bones
Enzymes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

The CYP3A4*18 genotype in the cytochrome P450 3A4 gene, a rapid metabolizer of sex steroids, is associated with low bone mineral density. / Kang, Y. S.; Park, S. Y.; Yim, C. H.; Kwak, H. S.; Gajendrarao, P.; Krishnamoorthy, Navaneethakrishnan; Yun, S. C.; Lee, K. W.; Han, K. O.

In: Clinical Pharmacology and Therapeutics, Vol. 85, No. 3, 01.03.2009, p. 312-318.

Research output: Contribution to journalArticle

Kang, Y. S. ; Park, S. Y. ; Yim, C. H. ; Kwak, H. S. ; Gajendrarao, P. ; Krishnamoorthy, Navaneethakrishnan ; Yun, S. C. ; Lee, K. W. ; Han, K. O. / The CYP3A4*18 genotype in the cytochrome P450 3A4 gene, a rapid metabolizer of sex steroids, is associated with low bone mineral density. In: Clinical Pharmacology and Therapeutics. 2009 ; Vol. 85, No. 3. pp. 312-318.
@article{2e750540615a402e8aa07dd6fef87a2f,
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.",
author = "Kang, {Y. S.} and Park, {S. Y.} and Yim, {C. H.} and Kwak, {H. S.} and P. Gajendrarao and Navaneethakrishnan Krishnamoorthy and Yun, {S. C.} and Lee, {K. W.} and Han, {K. O.}",
year = "2009",
month = "3",
day = "1",
doi = "10.1038/clpt.2008.215",
language = "English",
volume = "85",
pages = "312--318",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - The CYP3A4*18 genotype in the cytochrome P450 3A4 gene, a rapid metabolizer of sex steroids, is associated with low bone mineral density

AU - Kang, Y. S.

AU - Park, S. Y.

AU - Yim, C. H.

AU - Kwak, H. S.

AU - Gajendrarao, P.

AU - Krishnamoorthy, Navaneethakrishnan

AU - Yun, S. C.

AU - Lee, K. W.

AU - Han, K. O.

PY - 2009/3/1

Y1 - 2009/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=60349106806&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=60349106806&partnerID=8YFLogxK

U2 - 10.1038/clpt.2008.215

DO - 10.1038/clpt.2008.215

M3 - Article

VL - 85

SP - 312

EP - 318

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 3

ER -