RT Journal Article
SR Electronic
T1 Methylation of CAR is involved in the Suppression of CYP2C19 in HBV-associated Hepatocellular Carcinoma
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.116.070243
DO 10.1124/dmd.116.070243
A1 Xiaojing Tang
A1 Lele Ge
A1 Zhongjian Chen
A1 Sisi Kong
A1 Wenhui Liu
A1 Yingchun Xu
A1 Su Zeng
A1 Shuqing Chen
YR 2016
UL http://dmd.aspetjournals.org/content/early/2016/07/20/dmd.116.070243.abstract
AB Hepatocellular carcinoma (HCC) is one of the most dangerous malignancies, which represents a major international health problem due to its increasing incidence and high mortality rate. It has been known that the progression of HCC involves a genome-wide alteration of epigenetic modifications, which leads to aberrant gene expression patterns. CYP2C19, which catalyzes the metabolism of a number of xenobiotics, is one of the most important members of the CYP450 superfamily. The activity of CYP2C19 was reported to be compromised in HCC, but the underlying mechanism remains unclear. In the present study, we evaluated the expression levels of CYP2C19 and its transcriptional factors by quantitative real-time PCR using mRNA extracted from both primary hepatocytes treated with 5-aza- 2'-deoxycytidine (5-aza-dC) and paired tumor and non-tumor liver tissues from hepatitis B virus (HBV)-infected patients. DNA methylation was examined by bisulfite sequencing (BSP) and methylation specific PCR (MSP). Results indicated that CYP2C19 could be regulated by e-box methylation of constitutive androstane receptor (CAR). The decreased expression of CYP2C19 in tumorouos tissues of HBV infected HCC patients is highly related with the down-regulated expression and promoter hypermethylation of CAR. Our study demonstrated that aberrant CAR methylation is involved in the regulation of CYP2C19 in HBV-related HCC and it may play a role during liver tumorigenesis.