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

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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.

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Acknowledgments

This work was supported by the Grant from Science and Technology Agency of Hunan Province (2014SK3011), the Scientific Research Funds of Pharmaceutical Association of Hunan Province (xy2015009), Key Projects of Scientific Research Funds in Central Hospital of Changsha in 2016 (CHCS201602), and the Grant from Special Major Science and Technology during the Twelfth Five-Year Plan of People’s Republic of China (2013ZX10005004).

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Authors and Affiliations

  1. Department of Pharmacy, Changsha Central Hospital, Changsha, 410004, Hunan, People’s Republic of China

    Li-chen Gao, Fang-qun Liu & Li Yang

  2. Department of Cardiology, Changsha Central Hospital, Changsha, 410004, Hunan, People’s Republic of China

    Hai-ying Dai & Ran Tao

  3. Tuberculosis Research Center, Pulmonary Hospital, Changsha Central Hospital, Changsha, 410004, Hunan, People’s Republic of China

    Shi-Peng Cao

  4. Department of Oncology, Cancer Institute, Changsha Central Hospital, Changsha, 410004, Hunan, People’s Republic of China

    Di Wang

  5. Institute of Clinical Pharmacology, Central South University, Changsha, 410078, Hunan, People’s Republic of China

    Jie Tang

  6. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, Guangdong, People’s Republic of China

    Lin Cheng

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  1. Li-chen Gao
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Corresponding authors

Correspondence to Li-chen Gao or Li Yang.

Ethics declarations

The study protocol was approved by the ethics committee of Central South University, Changsha, Hunan, P. R. China (approved number: CTXY-110,003) and registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-TRC-11,001,285; Clinical Trial Registry website: http://www.chictr.org.cn /).

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Registration number: ChiCTR-TRC-11,001,285; Scientific title: The effect of ferulic acid on metabolites of hydroxy bupropion by CYP2B6 and POR gene; web site: http://www.chictr.org.cn/showproj.aspx?proj=8254.

Gao LC and Liu FQ contributed equally to the work.

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Gao, Lc., Liu, Fq., Yang, L. et al. 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 72, 1205–1213 (2016). https://doi.org/10.1007/s00228-016-2095-0

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