Distribution of chlordecone to liver plasma membranes and recovery from hepatobiliary dysfunction in rats.
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.
Rochelle
L G
LG
Oak Creek Laboratory of Biology, Department of Fisheries and Wildlife, Corvallis, OR 97331-3803.
Curtis
L R
LR
D000818:Animals; D001646:Bile / Q000378:metabolism / Q000502:physiology; D001660:Biliary Tract Diseases / Q000139:chemically induced* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability; D056486:Chemical and Drug Induced Liver Injury; D007631:Chlordecone / Q000032:analysis / Q000493:pharmacokinetics*; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D010635:Phenolphthaleins / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D002250:Carbon Radioisotopes; D010635:Phenolphthaleins; C016651:phenolphthalein glucuronide; D008353:Mannitol; D007631:Chlordecone