Melatonin attenuates lipopolysaccharide-induced down-regulation of pregnane X receptor and its target gene CYP3A in mouse liver.
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.
Xu
De-Xiang
DX
Institute of Clinical Pharmacology, Anhui Medical University, Hefei, P.R. China. xudex@mail.hf.ah.cn
Wei
Wei
W
Sun
Mei-Fang
MF
Wei
Ling-Zhen
LZ
Wang
Jian-Ping
JP
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D051544:Cytochrome P-450 CYP3A; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008550:Melatonin / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*
D017931:DNA Primers; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D001189:Aryl Hydrocarbon Hydroxylases; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D005978:Glutathione; D008550:Melatonin