Chlordecone is a potent in vitro inhibitor of oligomycin-insensitive Mg2+ -ATPase of rat bile canaliculi-enriched fraction.
The oligomycin-insensitive Mg2+ -ATPase (OIMATPase) of rat bile canaliculi-enriched fraction (BCEF) was inhibited by chlordecone (CD) in vitro (IC-50 = 25 microM). Kinetic analysis indicated noncompetitive inhibition. Inhibition of OIMATPase by filipin but not by atractyloside verified plasma membrane origin of activity. The cholestatic agents alpha-naphthyl isothiocyanate (ANIT) and taurolithocholate (TLC) decreased OIMATPase activity at in vitro concentrations of 33 and 162 microM, while taurocholate (a choleretic bile salt), ethynylestradiol, and manganese did not. Cholestatic drugs with primary intracellular sites of action (colchicine and phalloidin) were ineffective OIMATPase inhibitors in this concentration range. Inhibition of OIMATPase by N-ethylmaleimide (NEM) and dicyclohexylcarbodiimide (DCCD) indicated some H+ -ATPase activity in BCEF. In vitro sensitivity of OIMATPase of BCEF to CD, ANIT, and TLC suggested the bile canaliculus as a subcellular-level target for their cholestatic actions.
Curtis
L R
LR
Oak Creek Laboratory of Biology, Department of Fisheries and Wildlife, Oregon State University, Corvallis 97331.
D000818:Animals; D001648:Bile Canaliculi / Q000201:enzymology*; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology*; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors*; D007631:Chlordecone / Q000633:toxicity*; D066298:In Vitro Techniques; D007306:Insecticides / Q000633:toxicity*; D009840:Oligomycins / Q000494:pharmacology*; D051381:Rats
D007306:Insecticides; D009840:Oligomycins; D017301:Ca(2+) Mg(2+)-ATPase; D007631:Chlordecone