The P450 oxidoreductase (POR) rs2868177 and cytochrome P450 (CYP) 2B6*6 polymorphisms contribute to the interindividual variability in human CYP2B6 activity

To investigate whether single-nucleotide polymorphisms (SNPs) in the P450 oxidoreductase (POR) gene were correlated with interindividual variations in cytochrome P450 (CYP) 2B6 activity. Thirty-six healthy volunteers who tested CYP2B6 and POR polymorphisms were enrolled in the study. CYP2B6 activity was measured by bupropion hydroxylation with LC/MS/MS. The ratio of hydroxybupropion versus bupropion (AUC_hyd/AUC_bup) in terms of area under the time-concentration curve (AUC) was used to represent the CYP2B6 activity. The volunteers carrying CYP2B6*1/*1 showed a significantly higher mean AUC_hyd/ AUC_bup than those CYP2B6*1/*6 and CYP2B6*6/*6 variants (15.66 +/- A 1.65 vs. 9.25 +/- A 1.92, P = 0.008 and 15.66 +/- A 1.65 vs. 8.21 +/- A 1.74, P = 0.006, respectively). POR rs2868177 (6593 A > G) AA homozygotes showed a significantly lower mean AUC_hyd/ AUC_bup than that of POR rs2868177 AG heterozygotes or GG homozygotes (8.13 +/- A 1.37 vs. 12.15 +/- A 2.97, P = 0.005 and 8.13 +/- A 1.37 vs. 17.59 +/- A 3.25, P = 0.001, respectively). Moreover, POR rs2868177 AG heterozygotes and GG homozygotes showed a significantly increased mean AUC_hyd/AUC_bup than AA homozygotes in the CYP2B6*1/*1 and CYP2B6*6 carriers (16.40 +/- A 2.01 vs. 12.40 +/- A 1.45, P = 0.006 and 10.65 +/- A 1.47 vs. 6.54 +/- A 1.25, P = 0.004, respectively). Meanwhile, a strong correlation between the genetic variations (POR rs2868177 and CYP2B6*6) and AUC_hyd/ AUC_bup was found (P = 0.009 and P = 0.001, respectively). There was no significant difference in the mean AUC_hyd/AUC_bup among different POR *28 genotypes (P > 0.05). POR rs2868177 and CYP2B6*6 variants contribute to the interindividual variability in human CYP2B6 activity, which may affect the disposition and interaction of other CYP2B6 substrate drugs.