4[beta]-Hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians.
Diczfalusy, Ulf a; Miura, Jun b; Roh, Hyung-Keun c; Mirghani, Rajaa A. b; Sayi, Jane e; Larsson, Hanna a; Bodin, Karl G. a; Allqvist, Annika b; Jande, Mary e; Kim, Jong-Wook d; Aklillu, Eleni b; Gustafsson, Lars L. b; Bertilsson, Leif b
Pharmacogenetics and Genomics.
18(3):201-208, March 2008.
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Objectives: To study the potential endogenous marker of CYP3A activity, 4[beta]-hydroxycholesterol, and its relation to sex and the CYP3A5 geno/haplotypes and compare with CYP3A4/5 catalyzed 3-hydroxylation of quinine in the three major races.
Methods: The plasma concentration of 4[beta]-hydroxycholesterol was measured in healthy Tanzanians (n=138), Swedes (n=161) and Koreans (n=149) by gas chromatography-mass spectrometry. The metabolic ratio of quinine/3-hydroxyquinine in plasma 16-h post dose was determined by high performance liquid chromatography, previously reported in Tanzanians and Swedes, and now also in Koreans. The participants were genotyped for relevant alleles of CYP3A5.
Results: The mean plasma concentrations of 4[beta]-hydroxycholesterol in Koreans, Swedes and Tanzanians were 29.3, 26.8 and 21.9 ng/ml, respectively (P<0.01 between all three populations). Within all three populations there were significant differences in 4[beta]-hydroxycholesterol levels between the CYP3A5 genotypes. Women had higher concentrations than men, but the difference was only significant in Tanzanians (P<0.001) and Koreans (P<0.00001). The quinine/3-hydroxyquinine metabolic ratio was significantly different in all three populations with the highest CYP3A activity in Koreans and the lowest in Tanzanians. Korean women had a lower metabolic ratio than men (P<0.00001). Significant correlations between 4[beta]-hydroxycholesterol and quinine 3-hydroxylation were found in Tanzanians and Koreans.
Conclusion: Clear differences in the activity of both CYP3A4 and CYP3A5 were shown in the three major human races. Both 4[beta]-hydroxycholesterol and quinine/3-hydroxyquinine metabolic ratio showed a higher CYP3A activity in women than in men. The results give strong evidence that the plasma concentration of 4[beta]-hydroxycholesterol may be used as an endogenous marker of CYP3A activity (CYP3A4 5).
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