title: Reversing effects of lignans on CCl4-induced hepatic CYP450 down regulation by attenuating oxidative stress.
abstract: Oxidative stress has been proved to be a critical reason of regulating CYP450s under hepatic injury status. The study was aimed to investigate the effect of pretreatment of schisandra lignan extracts (SLE) and dimethyl diphenyl bicarboxylate (DDB) on expressions and activities of the main liver P450 isoenzymes in CCl4 induced liver injury rats and their anti-oxidative effects on both CCl4 induced liver injury rats and a CCl4 induced HepG2 cell injury model. Acute experimental liver injury induced by CCl4 caused drastically decreasing activities of the main liver P450 isoenzymes such as CYP1A2, CYP2C6, CYP2E1 and CYP3A2, as well as their protein expressions. Pretreatment of SLE (500 mg/kg) and DDB (200 mg/kg) twice a day for three days significantly decreased the losses of activities of CYP1A2, CYP2C6, CYP2E1 and CYP3A2. Similar results were observed in protein expressions. In addition, in the CCl4 induced HepG2 cells injury model and the CYP3A activity level correlated well with ROS level in several ingredients of SLE treated groups, especially in γ-schisandrin group. These results indicated that the reversion of P450 after SLE/DDB treatment were, on one hand, due to hepatoprotective effects of these lignans on livers; on the other hand, due to their regulation of P450 through anti-oxidative effect and γ-schisandrin might be the most powerful ingredient of SLE. Also, there might be potential interactions between SLE or DDB and co-administered medicines and it is necessary to adjust the dosage of co-administrated medicines in clinical medication of liver disease.
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
authors.forename: Cen
authors.initials: C
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
authors.forename: An
authors.initials: A
authors.lastname: Kang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China. Electronic address: guangjiwang@hotmail.com.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000633:toxicity; D034242:Cyclooctanes; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D017705:Lignans / Q000302:isolation & purification / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000517:prevention & control; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000302:isolation & purification / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D032141:Schisandra / Q000737:chemistry*
chemical_list: D000975:Antioxidants; D034242:Cyclooctanes; D004149:Dioxoles; D017705:Lignans; D010936:Plant Extracts; D011083:Polycyclic Compounds; C015499:schizandrin B; C041398:7,7'-dimethoxy-(4,4'-bi-1,3-benzodioxole)-5,5'-dicarboxylic acid dimethyl ester; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride
keywords: CYP450; Lignan; Liver injury; Oxidative stress