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  • Title: Effects of the selected cytochrome P450 oxidoreductase genetic polymorphisms on cytochrome P450 2B6 activity as measured by bupropion hydroxylation.
    Author: Lv J, Hu L, Zhuo W, Zhang C, Zhou H, Fan L.
    Journal: Pharmacogenet Genomics; 2016 Feb; 26(2):80-7. PubMed ID: 26580670.
    Abstract:
    BACKGROUND/AIM: Cytochrome P450 oxidoreductase (POR) is required for drug metabolism by all microsomal cytochrome P450 (CYP) enzymes. The aim of this study was to investigate whether single-nucleotide polymorphisms in the POR gene were correlated with interindividual variations in CYP2B6 activity, as measured by bupropion hydroxylation. METHODS: Thirty-five healthy individuals with selected CYP2B6 and POR polymorphisms were involved in the clinical study. The activity of CYP2B6 was evaluated on the basis of the area under the time-concentration curve (AUC) ratio of hydroxybupropion versus bupropion (AUC_hyd/AUC_bup). RESULTS: Individuals carrying CYP2B6*1/*1 showed a significantly higher mean AUC_hyd/AUC_bup than individuals carrying the CYP2B6*1/*6 and CYP2B6*6/*6 variants (17.1 ± 6.23 vs. 10.3 ± 4.53, P = 0.003 and 17.1 ± 6.23 vs. 9.41 ± 2.84, P = 0.002, respectively). POR g.6593A>G (rs2868177) AA homozygotes showed a significantly lower mean AUC_hyd/AUC_bup than POR g.6593A>G AG heterozygotes or GG homozygotes (8.54 ± 2.65 vs. 14.9 ± 6.06, P = 0.005 and 8.54 ± 2.65 vs. 16.8 ± 6.45, P = 0.002, respectively). Moreover, POR g.6593A>G AA homozygotes had a significantly lower mean AUC_hyd/AUC_bup than the POR g.6593A>G AG/GG genotypes in the CYP2B6*1/*1, CYP2B6*1/*6 and CYP2B6*6/*6 groups (10.9 ± 1.82 vs. 19.7 ± 5.53, P < 0.001; 6.18 ± 0.284 vs. 12.1 ± 4.31, P = 0.011; and 6.94 ± 1.48 vs. 10.9 ± 2.39, P = 0.043, respectively). There was no significant difference in the mean AUC_hyd/AUC_bup among different POR c.1508C>T (*28 or rs1057868) genotypes, even after the effect of CYP2B6*6 was excluded. CONCLUSION: These results indicate, for the first time, that the POR g.6593A>G polymorphism significantly influences CYP2B6 activity, as measured by bupropion hydroxylation, in humans, and the CYP2B6*6 and POR g.6593A>G polymorphisms might be considered simultaneously for the individualized therapy with CYP2B6 substrate drugs such as bupropion.
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