title: Effects of glycyrrhizin on biliary transport and hepatic levels of glutathione in rats.
abstract: The purpose of the current study was to determine whether glycyrrhizin (GL) maintains hepatic glutathione (GSH) levels by inhibiting GSH biliary secretion in normal rats. The effects of glycyrrhizin on hepatic glutathione content, bile flow and biliary secretion of glutathione were examined. Because glutathione is a substrate for multidrug resistance associated protein-2 (Mrp2/ABCC2), the inhibitory effects of GL on Mrp2 in isolated perfused rat liver and in Mrp2-expressing Sf9 membrane vesicles were also examined using the Mrp2 substrate methotrexate (MTX) and estradiol-17-β-glucuronide (E2 17G). The hepatic content of glutathione in rats following GL perfusion (43.7 µmol/l) in isolated liver perfusion and GL intravenous treatment (25 mg/kg) was significantly higher than that for the control. A marked and dose-dependent decrease in the excretion of glutathione was observed. In addition, the secretion rate of MTX was decreased by 57% in isolated liver perfusion in GL-treated rats. Moreover the ATP-dependent uptake of E2 17G by Mrp2 membrane vesicles was decreased by 75.9% in the 20 µm GL group and by 60.5% in the 2 µm GL group. In conclusion, glycyrrhizin increases hepatic glutathione content possibly through inhibition of Mrp2 which then reduces the biliary excretion of glutathione.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Xu
authors.forename: Xueying
authors.initials: X
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Liu
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Davey
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000494:pharmacology*; D001646:Bile / Q000737:chemistry; D001659:Biliary Tract / Q000378:metabolism*; D001693:Biological Transport, Active; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005978:Glutathione / Q000378:metabolism*; D019695:Glycyrrhizic Acid / Q000097:blood / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
chemical_list: D000893:Anti-Inflammatory Agents; D004958:Estradiol; D005978:Glutathione; D019695:Glycyrrhizic Acid; D008727:Methotrexate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C025483:estradiol-17 beta-glucuronide