DISTRIBUTION OF CHLORDECONE TO LIVER PLASMA-MEMBRANES AND RECOVERY FROM HEPATOBILIARY DYSFUNCTION IN RATS

Chlordecone (CD) impairs biliary excretion of organic anions (includin g 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 hepatobiliar y dysfunction is dependent on CD concentration in liver plasma membran es where it inhibits active transport in vitro. Rats were treated by g avage (0 or 60 mg CD/kg in corn oil) 24 or 72 h prior to bile duct can nulation. Biliary excretion of PG, a marker of hepatic organic anion t ransport, and [C-14]mannitol, a marker of passive transcellular permea bility, was determined. Biliary excretion of PG decreased approximatel y 25% in rats 24 h after CD treatment, however rats recovered control PG excretion rates 72 h after CD treatment: Recovery of PG excretion o ccurred despite higher liver homogenate [C-14]CD concentrations at 72 h than at 24 h after [C-14]CD treatment. Biliary clearance of [C-14]ma nnitol decreased both 24 h and 72 h after treatment. Even though the a mount of [C-14]CD retained in the liver was greater at 72 h than at 24 h after treatment, the concentration of [C-14]CD in isolated liver pl asma membranes (LPM) was the same (3.5-3.9 nmol/mg protein) at both ti mes. 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 corre lation between recovery from CD-induced hepatobiliary dysfunction and whole liver accumulation. Altered subcellular [C-14]CD distribution (r educed LPM-to-homogenate concentration ratio) was coincident with reco very.