title: The P450 oxidoreductase (POR) rs2868177 and cytochrome P450 (CYP) 2B6*6 polymorphisms contribute to the interindividual variability in human CYP2B6 activity.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacy, Changsha Central Hospital, Changsha, 410004, Hunan, People's Republic of China. gonedog1224@hotmail.com.
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Gao
authors.affiliation: Department of Pharmacy, Changsha Central Hospital, Changsha, 410004, Hunan, People's Republic of China.
authors.forename: Fang-Qun
authors.initials: FQ
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Changsha Central Hospital, Changsha, 410004, Hunan, People's Republic of China. yl7618@126.com.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, Guangdong, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, Changsha Central Hospital, Changsha, 410004, Hunan, People's Republic of China.
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Dai
authors.affiliation: Department of Cardiology, Changsha Central Hospital, Changsha, 410004, Hunan, People's Republic of China.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.affiliation: Tuberculosis Research Center, Pulmonary Hospital, Changsha Central Hospital, Changsha, 410004, Hunan, People's Republic of China.
authors.forename: Shi-Peng
authors.initials: SP
authors.lastname: Cao
authors.affiliation: Department of Oncology, Cancer Institute, Changsha Central Hospital, Changsha, 410004, Hunan, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology, Central South University, Changsha, 410078, Hunan, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
mesh_terms: D000328:Adult; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D016642:Bupropion / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics* / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D006900:Hydroxylation; D008297:Male; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C000602470:POR protein, human; C580748:hydroxybupropion; D016642:Bupropion; D003577:Cytochrome P-450 Enzyme System; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6
keywords: Bupropion hydroxylation; CYP2B6; Interindividual variations; P450 oxidoreductase; Polymorphism