The nuclear receptor REV-ERBα regulates CYP2E1 expression and acetaminophen hepatotoxicity
Creators: name: Zhang, Li
name: Zhang, Fugui
name: Xiao, Yifei
name: Du, Jianhao
name: Zhang, Xingwang
name: Chen, Min
name: Wu, Baojian
Publisher: name: Taylor & Francis
Year: 2022
Subjects: subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: Molecular Biology
subject: Pharmacology
subject: Environmental Sciences not elsewhere classified
subject: Chemical Sciences not elsewhere classified
subject: Science Policy
subject: Cancer
subject: Computational Biology

description: 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 <i>in vivo</i> (using <i>Rev-erbα</i><sup>-/-</sup> mice) and <i>in vitro</i> (using AML12 and HepG2 cells). <i>In vitro</i> microsomal CYP2E1 activity was probed using its specific substrate <i>p</i>-nitrophenol. Pharmacokinetic and acute toxicity studies were performed with <i>Rev-erbα</i><sup>−/−</sup> and wild-type mice after APAP administration.We found that <i>Rev-erbα</i> ablation led to decreases in hepatic CYP2E1 expression and activity in mice. In line with this, APAP-induced hepatotoxicity was attenuated in <i>Rev-erbα-</i>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 <i>Cyp2e1</i> transcription and expression through repression of DEC2.In conclusion, REV-ERBα positively regulates CYP2E1 expression in mice, thereby affecting APAP metabolism and hepatotoxicity. 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 <i>in vivo</i> (using <i>Rev-erbα</i><sup>-/-</sup> mice) and <i>in vitro</i> (using AML12 and HepG2 cells). <i>In vitro</i> microsomal CYP2E1 activity was probed using its specific substrate <i>p</i>-nitrophenol. Pharmacokinetic and acute toxicity studies were performed with <i>Rev-erbα</i><sup>−/−</sup> and wild-type mice after APAP administration. We found that <i>Rev-erbα</i> ablation led to decreases in hepatic CYP2E1 expression and activity in mice. In line with this, APAP-induced hepatotoxicity was attenuated in <i>Rev-erbα-</i>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 <i>Cyp2e1</i> transcription and expression through repression of DEC2. In conclusion, REV-ERBα positively regulates CYP2E1 expression in mice, thereby affecting APAP metabolism and hepatotoxicity.