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

Eur J Clin Pharmacol. 2016 Oct;72(10):1205-1213. doi: 10.1007/s00228-016-2095-0. Epub 2016 Jul 20.

Abstract

Aim: To investigate whether single-nucleotide polymorphisms (SNPs) in the P450 oxidoreductase (POR) gene were correlated with interindividual variations in cytochrome P450 (CYP) 2B6 activity.

Methods: 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.

Results: 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 ± 1.65 vs. 9.25 ± 1.92, P = 0.008 and 15.66 ± 1.65 vs. 8.21 ± 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 ± 1.37 vs. 12.15 ± 2.97, P = 0.005 and 8.13 ± 1.37 vs. 17.59 ± 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 ± 2.01 vs. 12.40 ± 1.45, P = 0.006 and 10.65 ± 1.47 vs. 6.54 ± 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).

Conclusion: 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.

Keywords: Bupropion hydroxylation; CYP2B6; Interindividual variations; P450 oxidoreductase; Polymorphism.

Publication types

  • Controlled Clinical Trial

MeSH terms

  • Adult
  • Area Under Curve
  • Asian People / genetics
  • Bupropion / analogs & derivatives
  • Bupropion / blood
  • Bupropion / pharmacokinetics
  • Cytochrome P-450 CYP2B6 / genetics*
  • Cytochrome P-450 CYP2B6 / metabolism*
  • Cytochrome P-450 Enzyme System / genetics*
  • Gene Frequency
  • Genotype
  • Healthy Volunteers
  • Humans
  • Hydroxylation
  • Male
  • Polymorphism, Single Nucleotide
  • Young Adult

Substances

  • POR protein, human
  • hydroxybupropion
  • Bupropion
  • Cytochrome P-450 Enzyme System
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6