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Diczfalusy, Ulf; Miura, Jun; Roh, Hyung-Keun; Mirghani, Rajaa A; Sayi, Jane; Larsson, Hanna; Bodin, Karl G; Allqvist, Annika; Jande, Mary; Kim, Jong-Wook; Aklillu, Eleni; Gustafsson, Lars L; Bertilsson, Leif
Pharmacogenetics and genomics, 2008-March, Letnik: 18, Številka: 3Journal Article
OBJECTIVESTo study the potential endogenous marker of CYP3A activity, 4β-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. METHODSThe plasma concentration of 4β-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. RESULTSThe mean plasma concentrations of 4β-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 4β-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 4β-hydroxycholesterol and quinine 3-hydroxylation were found in Tanzanians and Koreans. CONCLUSIONClear differences in the activity of both CYP3A4 and CYP3A5 were shown in the three major human races. Both 4β-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 4β-hydroxycholesterol may be used as an endogenous marker of CYP3A activity (CYP3A4+5).
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