The nuclear receptor REV-ERBα regulates CYP2E1 expression and acetaminophen hepatotoxicity

• Published in: Xenobiotica Vol. 52; no. 6; pp. 633 - 643
• Main Authors: Zhang, Li, Zhang, Fugui, Xiao, Yifei, Du, Jianhao, Zhang, Xingwang, Chen, Min, Wu, Baojian
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 03.06.2022
• Subjects: APAP; CYP2E1; DEC2; hepatotoxicity; REV-ERBα
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498254.2022.2128934

CYP2E1 plays an important role in drug metabolism and drug-induced hepatotoxicity. Here, we aimed to investigate a potential role for the nuclear receptor REV-ERBα in regulation of CYP2E1 expression and acetaminophen (APAP)-induced hepatotoxicity, and to determine the underlying mechanisms. Regulatory effects of REV-ERBα on CYP2E1 expression were assessed in vivo (using Rev-erbα -/- mice) and in vitro (using AML12 and HepG2 cells). In vitro microsomal CYP2E1 activity was probed using its specific substrate p-nitrophenol. Pharmacokinetic and acute toxicity studies were performed with Rev-erbα −/− and wild-type mice after APAP administration. We found that Rev-erbα ablation led to decreases in hepatic CYP2E1 expression and activity in mice. In line with this, APAP-induced hepatotoxicity was attenuated in Rev-erbα-deficient mice. The attenuated toxicity was due to down-regulation of APAP metabolism mediated by CYP2E1, which was evidenced by a decrease in formation of the toxic intermediate metabolite NAPQI (i.e. reduced APAP-cysteine and APAP-N-acetylcysteine levels). Furthermore, positive regulation of CYP2E1 expression by REV-ERBα was confirmed in both AML12 and HepG2 cells. Based on luciferase reporter assays, it was found that REV-ERBα regulated Cyp2e1 transcription and expression through repression of DEC2. In conclusion, REV-ERBα positively regulates CYP2E1 expression in mice, thereby affecting APAP metabolism and hepatotoxicity.