phenolphthalein-glucuronide and Liver-Diseases

There are several reports on the biliary excretion of bile acids and organic anions in zone 1- and zone 3-injured rat liver, but the results are controversial. In order to dissolve the discrepancy between previous works about the role of hepatic zonation on the hepatic handling of the substrates of multidrug resistance protein 2, the biliary excretion of sulfated bile acids, pravastatin and phenolphthalein glucuronide was studied in zone 1- and zone 3-injured rats.. Zone 1 and zone 3 injury were caused by allyl alcohol and bromobenzene, respectively. Bile acid sulfates, pravastatin and phenolphthalein glucuronide were administered i.v. to bile duct-cannulated rats, and their biliary excretion was studied.. The biliary excretion of a tracer dose of taurolithocholate-3-sulfate and its excretory maximum were unchanged in zone 1 injury, but were diminished in zone 3 injury, whereas the biliary excretion of taurochenodeoxycholate-3-sulfate was unchanged in zone 1 and zone 3 injury. The biliary excretion of pravastatin and phenolphthalein glucuronide was markedly decreased only in zone 3 injury, whereas the excretory maximum of phenolphthalein glucuronide was decreased in both zone 1 and zone 3 injury.. These findings indicate that zone 3 is important for the biliary excretion of substrates of multidrug resistance protein 2.

Topics: Animals; Anions; ATP-Binding Cassette Transporters; Bile; Bile Acids and Salts; Biliary Tract; Biological Transport; Bromobenzenes; Chemical and Drug Induced Liver Injury; Liver; Liver Diseases; Male; Phenolphthaleins; Pravastatin; Propanols; Rats; Rats, Sprague-Dawley; Taurolithocholic Acid

Chlordecone (CD) impairs biliary excretion of organic anions (including phenolphthalein glucuronide (PG), imipramine polar metabolites, and taurocholate) without evidence of hepatocellular necrosis in rats. In this study we investigated the hypothesis that CD-induced hepatobiliary dysfunction is dependent on CD concentration in liver plasma membranes where it inhibits active transport in vitro. Rats were treated by gavage (0 or 60 mg CD/kg in corn oil) 24 or 72 h prior to bile duct cannulation. Biliary excretion of PG, a marker of hepatic organic anion transport, and [14C]mannitol, a marker of passive transcellular permeability, was determined. Biliary excretion of PG decreased approximately 25% in rats 24 h after CD treatment, however rats recovered control PG excretion rates 72 h after CD treatment. Recovery of PG excretion occurred despite higher liver homogenate [14C]CD concentrations at 72 h than at 24 h after [14C]CD treatment. Biliary clearance of [14C]mannitol decreased both 24 h and 72 h after treatment. Even though the amount of [14C]CD retained in the liver was greater at 72 h than at 24 h after treatment, the concentration of [14C]CD in isolated liver plasma membranes (LPM) was the same (3.5-3.9 nmol/mg protein) at both times. There was a significant reduction in 5'-nucleotidase activity of LPM at 24 h but not at 72 h after CD. This study demonstrated no correlation between recovery from CD-induced hepatobiliary dysfunction and whole liver accumulation. Altered subcellular [14C]CD distribution (reduced LPM-to-homogenate concentration ratio was coincident with recovery.

Topics: Animals; Bile; Biliary Tract Diseases; Carbon Radioisotopes; Cell Membrane; Cell Membrane Permeability; Chemical and Drug Induced Liver Injury; Chlordecone; Liver; Liver Diseases; Male; Mannitol; Phenolphthaleins; Rats; Rats, Sprague-Dawley