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Combined Influence of Genetic Polymorphism and DNA Methylation on ABCB1 Expression and Function in Healthy Chinese Males

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Abstract

Background and Objectives

It is well known that the expression and function of ATP-binding cassette transporter B1 (ABCB1) show high interindividual variability, but the reasons have not yet been fully elucidated. In this study, combined influence of genetic polymorphism and DNA methylation on ABCB1 mRNA expression and digoxin pharmacokinetics in healthy Chinese males was analyzed.

Methods

A total of 93 subjects who were homozygous for the ABCB1 1236-2677-3435 TTT or CGC haplotype were enrolled in this study. DNA methylation status of the ABCB1 promoter and ABCB1 mRNA expression level in exfoliated intestinal epithelial cells were analyzed using bisulfite sequencing PCR and real-time PCR. The pharmacokinetics of digoxin in subjects were investigated after administration of a single oral dose of digoxin 0.5 mg.

Results

The DNA methylation levels of ABCB1 promoter showed no significant difference between TTT/TTT and CGC/CGC carriers (P = 0.54). Subjects with TTT/TTT haplotype pair and high methylation status (TTT/TTT-HM) showed a significantly lower ABCB1 mRNA level compared to other subjects. Compared with TTT/TTT-HM subgroup, the area under the plasma concentration–time curve from time zero to 72 h (AUC0–72) of digoxin was decreased by 26.9 %, the maximum plasma concentration (C max) was decreased by 25 % and the apparent oral clearance (CL/F) was increased by 21.2 % in CGC/CGC-LM subgroup. The values of time to maximum concentration (t max) and terminal elimination half-life (t 1/2) showed no significant difference.

Conclusions

Both genetic polymorphism and DNA methylation variation should be taken into consideration to explain the interindividual variability in ABCB1 expression and function more clearly.

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Authors and Affiliations

  1. Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Lan-Xiang Wu, Chun-Jie Wen, Ying Li, Ying-Ying Shao, Zhu Yang & Hong-Hao Zhou

  2. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200090, People’s Republic of China

    Hong-Bo Zhao

  3. Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, 410078, People’s Republic of China

    Hong-Hao Zhou

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  1. Lan-Xiang Wu
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Correspondence to Lan-Xiang Wu.

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Funding

This study was funded by the National Scientific Foundation of China (No. 81102511, 81473284), Natural Science Foundation of Chongqing (No. cstc2011jjA10004), Postdoctoral Science Foundation of China (No. 2 011M500669), Special Postdoctoral Research Foundation of Chongqing (No.Yu xm201102007), Medical Scientific Research Foundation of Chongqing, China (No. 2013-2-150) and Funds for outstanding young scholars in Chongqing Medical University (No. CYYQ201301, 4101070044).

Conflict of interest

WLX, ZHB, WCJ, LY, SYY, YZ and ZHH declare no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the independent ethics committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Wu, LX., Zhao, HB., Wen, CJ. et al. Combined Influence of Genetic Polymorphism and DNA Methylation on ABCB1 Expression and Function in Healthy Chinese Males. Eur J Drug Metab Pharmacokinet 42, 627–634 (2017). https://doi.org/10.1007/s13318-016-0376-8

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  • DOI: https://doi.org/10.1007/s13318-016-0376-8

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