CHLORDECONE PRETREATMENT ALTERS [C-14] CHLORDECONE AND [C-14] CHOLESTEROL TRANSPORT KINETICS IN THE PERFUSED-RAT-LIVER

Previous work demonstrated that pretreatment of mice with low doses of the organochlorine insecticide chlordecone (CD) altered the tissue di sposition of a subsequent [C-14]CD or [C-14]- cholesterol challenge do se. The profile of these changes was consistent with the induction of a protein integral to hepatic CD/cholesterol turnover. The present stu dy was undertaken to confirm similar in vivo effects in the rat and to analyze potential CD-induced changes in hepatic transport kinetics in the perfused rat liver. For in vivo experiments, male, Sprague-Dawley rats were treated with CD (5, 15, or 40 mg/kg) and challenged 3 or 7 days later with a 5 mg/kg [(1)4C]CD tracer dose. Rats challenged 3 day s after treatment and evaluated 16 hr later showed a dose-dependent de crease in hepatic [C-14]CD relative to controls. This decrease could n ot be attributed to alterations in liver mass or total liver lipid. Fo r kinetics studies, rats received 15 mg/kg CD and livers were perfused 3 days later. Following a brief (5-7 min) single-pass perfusion, the perfusate was replaced with recirculating buffer containing albumin-bo und [H-3]oleic acid or high-density lipoprotein-bound [C-14]CD or [C-1 4]cholesterol. Livers from pretreated animals had significantly decrea sed rates of [C-14]CD and [C-14]cholesterol uptake. Efflux of [C-14]CD and biliary excretion of [C-14]cholesterol were increased. No changes were observed in uptake or biliary excretion of [H-3]oleic acid. SDS- PAGE of hepatic cytosol revealed an enhanced band intensity correspond ing to a M(r) of 25,600 in livers from pretreated rats. These results are supportive of a competitive interaction between cholesterol and CD for proteins associated with hepatocellular transport and excretion a nd suggest that CD pretreatment may have an inductive effect on these proteins. (C) 1994 Society of Toxicology.