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

The Pharmacogenomics Journal volume 11, pages 130–137 (2011)Cite this article

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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 4β-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 4β-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 4β-hydroxycholesterol level was 35.4 ng ml−1. The mean 4β-hydroxycholesterol level (P=0.0001) and the 4β-hydroxycholesterol/cholesterol ratio (P=0.004) were higher in women than in men. CYP3A5 genotype significantly correlated with the plasma 4β-hydroxycholesterol concentration (P=0.003) and 4β-hydroxycholesterol/cholesterol ratio (P=0.0002). The omeprazole/omeprazole sulfone ratio was significantly correlated with 4β-hydroxycholesterol and 4β-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 4β-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.

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Acknowledgements

This study was supported by grant from Addis Ababa University, SIDA/SAREC Grant no. HIV-2006-031, SWE 2007-270, EDCTP Grant no. CT.2005.32030.001, Torsten och Ragnar Söderbergs Stiftelser, ALF (SLL 581107) and Swedish Research Council, Medicine (3902).

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Addis Ababa University, Addis Ababa, Ethiopia

    E Gebeyehu & E Engidawork

  2. Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

    A Bijnsdorp, A Aminy & E Aklillu

  3. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    U Diczfalusy

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Correspondence to E Aklillu.

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Gebeyehu, E., Engidawork, E., Bijnsdorp, A. et al. Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians. Pharmacogenomics J 11, 130–137 (2011). https://doi.org/10.1038/tpj.2010.16

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