Melatonin attenuates lipopolysaccharide‐induced down‐regulation of pregnane X receptor and its target gene CYP3A in mouse liver

Abstract

Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that regulates target gene transcription in a ligand-dependent manner. Our earlier study indicated that reactive oxygen species contribute to lipopolysaccharide (LPS)-induced down-regulation of PXR and its target gene CYP3A in mouse liver. Melatonin is a powerful endogenous antioxidants. In this study, we investigated the effects of melatonin on LPS-induced down-regulation of PXR and CYP3A in mouse liver. Mice were intraperitoneally administrated different doses of melatonin before and/or after LPS treatment. PXR and CYP3A11 mRNA levels were measured using RT-PCR. Erythromycin N-demethylase (ERND) was used as an indicator of CYP3A catalytic activity. Results indicated that melatonin significantly attenuated LPS-induced down-regulation of PXR and CYP3A11 mRNA levels in a dose-dependent manner. Repeated doses of melatonin (10 mg/kg) treatments also significantly attenuated LPS-induced down-regulation of dexamethasone-inducible CYP3A11 mRNA level and ERND activity in mouse liver. In addition, the present study also shows that melatonin significantly increased hepatic superoxide dismutase, Se-dependent glutathione peroxidase, glutathione reductase and catalase activities and glutathione levels in LPS-treated mice. These findings suggest that melatonin may exert its protective effects on LPS-induced down-regulation of PXR and CYP3A via counteracting LPS-induced oxidative stress in mouse liver.