Impaired biliary excretion of taurocholate associated with increased biliary tree permeability in mirex- or...

Impaired biliary excretion of exogenously provided xenobiotic metabolites was demonstrated previously after pre-exposure of rats to mirex (MX) or chlordecone (CD). This toxicity was studied further in pentobarbital-anesthetized rats, cannulated at the common bile duct. We found reduced biliary excretion rates for exogenous [14C]taurocholic acid (3 or 10 mumol/kg bolus) after 15-day dietary pretreatment of male rats with 20 or 100 ppm of MX or CD. Hepatobiliary dysfunction was dose-dependent. Maximal reduction in excretory rate on a per gram of liver basis (50%) followed treatment with 100 ppm of MX. Biliary tree permeability was estimated to ascertain whether efflux of canalicular bile into the hepatic circulation explained hepatobiliary dysfunction. Bile-to-plasma concentration ratios for [3H]sucrose increased in parallel with MX- and CD-impaired biliary excretion. Modeling the relationship between bile flow and bile-to-plasma [3H]sucrose ratio indicated the site of increased permeability involved a paracellular pathway. Bile flow (on a per gram of liver basis) and biliary clearance of [14C]erythritol were both reduced by 100 ppm of these toxicants. The above effects occurred in the absence of substantial hepatocellular necrosis, whereas liver enlargement increased in a dose-dependent manner. Maximal liver enlargement (doubling of liver weight) resulted from 100 ppm of MX treatment. These results indicated that hepatobiliary dysfunction induced by MX and CD was at least partially explained by increased permeability of the biliary tree.