Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians by Gebeyehu E, Engidawork E, Bijnsdorp A, Aminy A, Diczfalusy U, Aklillu E in The pharmacogenomics journal (2010). PubMed

Abstract

The objectives of the this study were to assess the influence of CYP3A5 genotype and sex on the variability in total CYP3A activity and to compare 4beta-hydroxycholesterol and omeprazole sulfoxidation as phenotypic markers for CYP3A activity in Ethiopians. Healthy subjects (n=150) were genotyped for CYP3A5*3, *6 and *7 using allele-specific PCR and Taqman genotyping assays. Plasma levels of 4beta-hydroxycholesterol, 3 h post-dose omeprazole and omeprazole sulfone, were determined by gas chromatography-mass spectrometry and high performance liquid chromatography, respectively. The frequency of CYP3A5*1, (*)3, (*)6 and *7 was 20.5, 67.3, 12.2 and 0%, respectively. The mean plasma 4beta-hydroxycholesterol level was 35.4 ng ml(-1). The mean 4beta-hydroxycholesterol level (P=0.0001) and the 4beta-hydroxycholesterol/cholesterol ratio (P=0.004) were higher in women than in men. CYP3A5 genotype significantly correlated with the plasma 4beta-hydroxycholesterol concentration (P=0.003) and 4beta-hydroxycholesterol/cholesterol ratio (P=0.0002). The omeprazole/omeprazole sulfone ratio was significantly correlated with 4beta-hydroxycholesterol and 4beta-hydroxycholesterol/cholesterol ratio in CYP3A5*0/*0 genotypes but not in individuals carrying the CYP3A5*1 allele. No correlation of omeprazole/omeprazole sulfone ratio with sex or CYP3A5 genotype was observed. A clear gene-dose effect implies plasma 4beta-hydroxycholesterol level as a useful endogenous biomarker for total CYP3A activity (CYP3A5 plus CYP3A4) whereas the omeprazole/omeprazole sulfone ratio reflects mainly CYP3A4 activity. Sex and CYP3A5 genotype influence total CYP3A activity. Ethiopians display high total CYP3A activity and a unique distribution of CYP3A5 variant alleles not described hitherto.The Pharmacogenomics Journal advance online publication, 16 March 2010; doi:10.1038/tpj.2010.16.

[ hide abstract ]

Discussed In Paper