RT Journal Article
SR Electronic
T1 Methylation of the Constitutive Androstane Receptor Is Involved in the Suppression of CYP2C19 in Hepatitis B Virus–Associated Hepatocellular Carcinoma
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1643
OP 1652
DO 10.1124/dmd.116.070243
VO 44
IS 10
A1 Tang, Xiaojing
A1 Ge, Lele
A1 Chen, Zhongjian
A1 Kong, Sisi
A1 Liu, Wenhui
A1 Xu, Yingchun
A1 Zeng, Su
A1 Chen, Shuqing
YR 2016
UL http://dmd.aspetjournals.org/content/44/10/1643.abstract
AB 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.