Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

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 4 beta-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 4 beta-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 4b-hydroxycholesterol level was 35.4 ng ml(-1). The mean 4 beta-hydroxycholesterol level (P = 0.0001) and the 4 beta-hydroxycholesterol/cholesterol ratio (P = 0.004) were higher in women than in men. CYP3A5 genotype significantly correlated with the plasma 4 beta-hydroxycholesterol concentration (P = 0.003) and 4 beta-hydroxycholesterol/cholesterol ratio (P = 0.0002). The omeprazole/omeprazole sulfone ratio was significantly correlated with 4 beta-hydroxycholesterol and 4 beta-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 4 beta-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 (2011) 11, 130-137; doi:10.1038/tpj.2010.16; published online 16 March 2010