Chlordecone pretreatment alters [14C]chlordecone and [14C]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 disposition of a subsequent [14C]CD or [14C]cholesterol challenge dose. The profile of these changes was consistent with the induction of a protein integral to hepatic CD/cholesterol turnover. The present study 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 [14C]CD tracer dose. Rats challenged 3 days after treatment and evaluated 16 hr later showed a dose-dependent decrease in hepatic [14C]CD relative to controls. This decrease could not be attributed to alterations in liver mass or total liver lipid. For 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-bound [3H]oleic acid or high-density lipoprotein-bound [14C]CD or [14C]cholesterol. Livers from pretreated animals had significantly decreased rates of [14C]CD and [14C]cholesterol uptake. Efflux of [14C]CD and biliary excretion of [14C]cholesterol were increased. No changes were observed in uptake or biliary excretion of [3H]oleic acid. SDS-PAGE of hepatic cytosol revealed an enhanced band intensity corresponding to a M(r) of 25,600 in livers from pretreated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Gilroy
D J
DJ
Department of Fisheries and Wildlife, Oregon State University, Corvallis 97331.
Carpenter
H M
HM
Curtis
L R
LR
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000418:Albumins / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D007631:Chlordecone / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002784:Cholesterol / Q000493:pharmacokinetics*; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009829:Oleic Acids / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000418:Albumins; D008074:Lipoproteins; D009829:Oleic Acids; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D010088:Oxidoreductases; D015660:7-Alkoxycoumarin O-Dealkylase; D019363:Cytochrome P-450 CYP1A1; D007631:Chlordecone