标题：CYP2E1 and miRNA-378a-3p contribute to acetaminophen- or tripterygium glycosides-induced hepatotoxicity
作者：Chen, Keguang; Guo, Nan; Zhang, Rui; Wei, Chunmin; Guo, Ruichen
作者机构：[Chen, Keguang; Guo, Nan; Zhang, Rui; Guo, Ruichen] Shandong Univ, Inst Clin Pharmacol, Qilu Hosp, 107 West Wenhua Rd, Jinan 250012, Shandong, Peoples 更多
通讯作者：Guo, RC;Wei, CM
通讯作者地址：[Guo, RC]Shandong Univ, Inst Clin Pharmacol, Qilu Hosp, 107 West Wenhua Rd, Jinan 250012, Shandong, Peoples R China;[Wei, CM]Natl Med Prod Adm, Ctr Dr 更多
来源：BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
关键词：acetaminophen; hepatotoxicity; miR-378a-3p; tripterygium glycosides
摘要：Increased expression of CYP2E1 may represent the main factor contributing to oxidative stress-mediated liver damage in drug-induced liver injury (DILI). However, the regulation mechanism of CYP2E1 expression is poorly described. The present study was aimed to investigate the role of CYP2E1 in acetaminophen (APAP)- or tripterygium glycosides (TG)-induced hepatotoxicity as well as the regulation of CYP2E1 and miR-378a-3p expression by APAP or TG. Rats were randomly divided and treated with APAP, TG, chlormethiazole (CMZ), APAP + CMZ and TG + CMZ, respectively, for 4 weeks. Then, blood and liver samples were collected. Serum and hepatic biochemical parameters were measured using commercial kits. Liver histopathology was tested by H&E staining. Expression levels of CYP2E1 mRNA and miR-378a-3p were detected by qRT-PCR. CYP2E1 protein expression was determined by Western blot. Our results showed that CMZ effectively restored the hepatic histopathological changes, oxidative stress biomarkers and TNF-alpha levels induced by APAP or TG. CYP2E1 mRNA and/or protein expression levels were dramatically increased after chronic APAP or TG treatment, while this induction was significantly reversed by CMZ co-treatment. Of note, miR-378a-3p expression levels were significantly suppressed after APAP, TG and/or CMZ treatment. These results suggested that CYP2E1 were highly induced after chronic APAP or TG treatment, which in turn play an important role in APAP- or TG-induced hepatotoxicity. These inductions of CYP2E1 expression were probably carried out by inhibition of miR-378a-3p. Our findings might provide a new molecular basis for DILI.