Regulation of cyclophosphamide induced hepatotoxicity by REV-ERBα modifiers.

Introduction: Cyclophosphamide (CPA) is a widely used broad-spectrum antitumor drug with severe hepatotoxicity. Finding an effective way to mitigate the hepatotoxicity caused by CPA is a challenge in its clinical application.

Methods: In Rev-erbα knockout and wild-type mice, hepatotoxicity was evaluated by ALT, AST, and histopathological scores 4-h post dose of CPA (i.p. 300 mg/kg). CYP2B10 expression and pharmacokinetic behavior of CPA were also detected. SR9009 (i.p. 10 mg/kg) and Berberine (BBR, i.p. 50 mg/kg) were pre-administered to mice. Then, the measurements were carried out following the same procedures as previous. The regulation effects of SR9009 and BBR on CYP2B10 were validated using Hepa-1c1c7 cells.

Results: Firstly, REV-ERBα negatively regulated CPA-induced hepatotoxicity by altering the expression of CYP2B10 and CPA pharmacokinetics. Secondly, REV-ERBα agonists, SR9009 and BBR, increased REV-ERBα expression and alleviated hepatic toxicity of CPA. Furthermore, both SR9009 and BBR reduced expression of CYP2B10 and REV-ERBα target gene Bmal1 both in vivo and in vitro.

Conclusions: REV-ERBα agonists can significantly attenuate the hepatotoxicity of CPA by regulating CYP2B10. The discovery of REV-ERBα as novel regulator for CYP2B10 will help to establish new targets to improve drug efficacy or reduce toxicity.