title: Protective effects of hepatocellular canalicular conjugate export pump (Mrp2) on sodium arsenite-induced hepatic dysfunction in rats.
abstract: Arsenic is a double-edged sword to human health. The excretion of various organic anions into bile is mediated by an adenosine triphosphate-dependent conjugate export pump, which has been identified as the canalicular isoform of the multidrug resistance protein 2 (Mrp2). It has been proved that Mrp2 can transport arsenite in vitro, but its effects in vivo are not clear. The aim of this study was to investigate whether Mrp2 plays a role in exportation of arsenic in vivo and its protective effects on liver function. Mrp2 protein level in rat liver was determined by Western blot analysis. Total arsenic concentrations in whole blood and bile were measured using hydride generation atomic absorption spectrometry. Alanine aminotransferase (ALT) activity, aspartate aminotransferase activity (AST), glutathione peroxidase (GSH-PX) activity, malon dialdehyde (MDA) and total bilirubin were measured by biochemical assays. The morphological changes were observed by electron microscopy. Total arsenic levels in blood and bile of arsenite-treated rats were significantly higher than those of control rats (P<0.05) at all three different time points. The overexpression of Mrp2 was 36.61%, 32.36% and 12.73% at 2, 4 and 6 weeks, respectively (percentage of controls, P<0.05), which was significantly higher than controls. A positive correlation between Mrp2 expression level and total arsenic concentration in bile indicated that Mrp2 accelerated the transport of arsenic. Electron microscopy showed that microvilli of bile canaliculi became swollen and sparse. ALT and AST activities in serum were markedly raised at 6 weeks. MDA level in serum increased (P<0.05) and GSH-PX activity in serum decreased except for 2 weeks. Damage of liver function became worse following decreased expression of Mrp2. In conclusion, overexpression of Mrp2 may explain increased biliary excretion of arsenic and it may protect liver function.
authors.affiliation: Tianjin Centers for Disease Control and Prevention, Hedong District, Tianjin, PR China.
authors.forename: Guo-Xing
authors.initials: GX
authors.lastname: Li
authors.forename: Qiu-Ling
authors.initials: QL
authors.lastname: Pei
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: Ke-Ming
authors.initials: KM
authors.lastname: Liu
authors.forename: Ji-Sheng
authors.initials: JS
authors.lastname: Nie
authors.forename: Guang
authors.initials: G
authors.lastname: Han
authors.forename: Yu-Lan
authors.initials: YL
authors.lastname: Qiu
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Zhang
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001151:Arsenic / Q000097:blood; D020261:Arsenic Poisoning / Q000097:blood* / Q000473:pathology; D018053:Arsenites / Q000378:metabolism / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001648:Bile Canaliculi / Q000187:drug effects / Q000648:ultrastructure; D001663:Bilirubin / Q000097:blood; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000209:etiology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005979:Glutathione Peroxidase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D017670:Sodium Compounds / Q000378:metabolism / Q000633:toxicity*; D013054:Spectrophotometry, Atomic
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D018053:Arsenites; D004791:Enzyme Inhibitors; D017670:Sodium Compounds; C017947:sodium arsenite; D008315:Malondialdehyde; D005979:Glutathione Peroxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001151:Arsenic; D001663:Bilirubin