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Research ArticleArticle

Methylation of the Constitutive Androstane Receptor Is Involved in the Suppression of CYP2C19 in Hepatitis B Virus–Associated Hepatocellular Carcinoma

Xiaojing Tang, Lele Ge, Zhongjian Chen, Sisi Kong, Wenhui Liu, Yingchun Xu, Su Zeng and Shuqing Chen
Drug Metabolism and Disposition October 2016, 44 (10) 1643-1652; DOI: https://doi.org/10.1124/dmd.116.070243
Xiaojing Tang
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (X.T., W.L., Y.X., S.Z., S.C.); Department of Pharmacy, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China (L.G.); and Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, China (Z.C., S.K.)
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Lele Ge
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (X.T., W.L., Y.X., S.Z., S.C.); Department of Pharmacy, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China (L.G.); and Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, China (Z.C., S.K.)
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Zhongjian Chen
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (X.T., W.L., Y.X., S.Z., S.C.); Department of Pharmacy, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China (L.G.); and Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, China (Z.C., S.K.)
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Sisi Kong
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (X.T., W.L., Y.X., S.Z., S.C.); Department of Pharmacy, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China (L.G.); and Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, China (Z.C., S.K.)
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Wenhui Liu
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (X.T., W.L., Y.X., S.Z., S.C.); Department of Pharmacy, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China (L.G.); and Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, China (Z.C., S.K.)
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Yingchun Xu
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (X.T., W.L., Y.X., S.Z., S.C.); Department of Pharmacy, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China (L.G.); and Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, China (Z.C., S.K.)
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Su Zeng
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (X.T., W.L., Y.X., S.Z., S.C.); Department of Pharmacy, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China (L.G.); and Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, China (Z.C., S.K.)
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Shuqing Chen
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (X.T., W.L., Y.X., S.Z., S.C.); Department of Pharmacy, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China (L.G.); and Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, China (Z.C., S.K.)
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Abstract

Hepatocellular carcinoma (HCC), one of the most dangerous malignancies with an increasing incidence and a high mortality rate, represents a major international health problem. HCC progression is known to involve genome-wide alteration of epigenetic modifications, leading to aberrant gene expression patterns. The activity of CYP2C19, an important member of the cytochrome P450 superfamily, was reported to be compromised in HCC, but the underlying mechanism remains unclear. To understand whether epigenetic modification in HCC is associated with a change in CYP2C19 activity, we evaluated the expression levels of CYP2C19 and its transcription factors by quantitative real-time polymerase chain reaction using mRNA extracted from both primary hepatocytes and paired tumor versus nontumor liver tissues of patients infected with hepatitis B virus (HBV). DNA methylation was examined by bisulfite sequencing and methylation-specific polymerase chain reaction. Our results indicated that CYP2C19 could be regulated by e-box methylation of the constitutive androstane receptor (CAR). Decreased CYP2C19 expression in tumorous tissues of HBV-infected patients with HCC was highly correlated with suppressed expression and promoter hypermethylation of CAR. Our study demonstrates that aberrant CAR methylation is involved in CYP2C19 regulation in HBV-related HCC and may play a role in liver tumorigenesis.

Footnotes

    • Received February 27, 2016.
    • Accepted July 18, 2016.
  • This research was supported by the National Natural Science Foundation of China [Grant 81273578] and the Ministry of Science and Technology of China Natural Major Projects for Science and Technology Development [Grant 2012ZX09506001-004].

  • dx.doi.org/10.1124/dmd.116.070243.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (10)
Drug Metabolism and Disposition
Vol. 44, Issue 10
1 Oct 2016
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Research ArticleArticle

Epigenetic Study of CYP2C19 in Hepatocellular Carcinoma

Xiaojing Tang, Lele Ge, Zhongjian Chen, Sisi Kong, Wenhui Liu, Yingchun Xu, Su Zeng and Shuqing Chen
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1643-1652; DOI: https://doi.org/10.1124/dmd.116.070243

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Research ArticleArticle

Epigenetic Study of CYP2C19 in Hepatocellular Carcinoma

Xiaojing Tang, Lele Ge, Zhongjian Chen, Sisi Kong, Wenhui Liu, Yingchun Xu, Su Zeng and Shuqing Chen
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1643-1652; DOI: https://doi.org/10.1124/dmd.116.070243
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