title: Effects of the selected cytochrome P450 oxidoreductase genetic polymorphisms on cytochrome P450 2B6 activity as measured by bupropion hydroxylation.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: aDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University bInstitute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, People's Republic of China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Lv
authors.forename: Lei
authors.initials: L
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhuo
authors.forename: Congmin
authors.initials: C
authors.lastname: Zhang
authors.forename: Honghao
authors.initials: H
authors.lastname: Zhou
authors.forename: Lan
authors.initials: L
authors.lastname: Fan
mesh_terms: D016642:Bupropion / Q000378:metabolism*; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D006801:Humans; D006900:Hydroxylation; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic
chemical_list: D016642:Bupropion; D003577:Cytochrome P-450 Enzyme System; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D009251:NADPH-Ferrihemoprotein Reductase