title: Cytochrome P450 dysregulations in thioacetamide-induced liver cirrhosis in rats and the counteracting effects of hepatoprotective agents.
abstract: Dysregulations of cytochromes P450 (P450s) under liver injury have been extensively studied. However, little is known about the possible reversing effects of hepatoprotective agents, the understanding of which is of great importance in guiding clinical dosage adjustment for patients with liver injury. This study aims to investigate the dysregulation patterns of major P450s in thioacetamide (TAA)-induced liver cirrhosis in rats and the potential counteracting effects of hepatoprotective agents schisandra lignans extract (SLE) and dimethyl diphenyl bicarboxylate (DDB). TAA intoxications for 6 weeks induced apparent liver injury and dramatically reduced the hepatic protein expressions of CYP1A2, CYP2C6, CYP2E1, and CYP3A2 to 18, 71, 30, and 21% of that in the normal control, respectively. Both SLE and DDB treatments could significantly reverse the TAA-induced loss of P450 protein levels, which may be ascribed to their hepatoprotective effects and direct P450-inducing effects that have been confirmed in healthy rats. However, the recovery of enzyme activities of most P450s by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited NADPH-, time-, and concentration-dependent inactivating effects on all of the four major P450 isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided a good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA-induced dysregulated P450s.
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: Yuan
authors.initials: Y
authors.lastname: Xie
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Xilin
authors.initials: X
authors.lastname: Yao
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: An
authors.initials: A
authors.lastname: Kang
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.forename: Tong
authors.initials: T
authors.lastname: Xie
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
mesh_terms: D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004149:Dioxoles / Q000008:administration & dosage / Q000302:isolation & purification / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000627:therapeutic use*; D017705:Lignans / Q000737:chemistry; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010936:Plant Extracts / Q000302:isolation & purification / Q000627:therapeutic use; D020011:Protective Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D032141:Schisandra / Q000737:chemistry; D013255:Steroid 21-Hydroxylase / Q000096:biosynthesis; D013853:Thioacetamide / Q000633:toxicity; D013997:Time Factors
chemical_list: D004149:Dioxoles; D004365:Drugs, Chinese Herbal; D017705:Lignans; D008565:Membrane Proteins; D010936:Plant Extracts; D020011:Protective Agents; D013853:Thioacetamide; C041398:7,7'-dimethoxy-(4,4'-bi-1,3-benzodioxole)-5,5'-dicarboxylic acid dimethyl ester; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; C089877:Cyp2c6v1 protein, rat; C465260:Cyp3a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase