Chlordecone is a potent in vitro inhibitor of oligomycin‐insensitive mg²⁺ ‐ATPase of rat bile canaliculi–enriched fraction

Abstract

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.

Atsdr Evaluation of Health Effects of Chemicals

“…Possible explanations for the decreased excretion of metabolites in the bile include decreased uptake of substances by the hepatocyte (Teo and Vore, 1990), a decreased transfer of chemicals from the hepatocyte to the bile (Berman et al, 1986), and leaking of metabolites from the bile duct via a paracellular pathway (Curtis and Hoyt, 1984). The decrease in transfer may be due to decreased permeability of the canalicular membrane (Hewitt et al, 1986a) resulting from inhibition of the mg2+ATPase activity of the bile canaliculi Bansal and Desaiah, 1985;Curtis, 1988) or perturbations of plasma membrane (Rochelle et al, 1990).…”

Public health and chronic low chlordecone exposure in Guadeloupe, Part 1: hazards, exposure-response functions, and exposures

“…Chlordecone follows other toxicological pathways, mainly: induction of hepatic cytochrome [ 50 – 69 ]. inhibition of ATPase in the liver [ 52 – 55 , 69 ]. inhibition of ATPase in the brain [ 70 – 82 ].…”