In vivo relevance of Mrp2-mediated biliary excretion of the Amanita mushroom toxin demethylphalloin.
To determine which efflux carriers are involved in hepatic phalloidin elimination, hepatobiliary [(3)H]-demethylphalloin (DMP) excretion was studied in normal Wistar rats and in Mrp2 deficient TR(-) Wistar rats as well as in normal wild-type FVB mice, Mdr1a,b(-/-) knockout mice, and Bcrp1(-/-) knockout mice by in situ bile duct/gallbladder cannulation. A subtoxic dose of 0.03 mg DMP/kg b.w. was used, which did not induce cholestasis in any tested animal. Excretion of DMP into bile was not altered in Mdr1a,b(-/-) mice or in Bcrp1(-/-) mice compared with wild-type FVB mice. Whereas 17.6% of the applied dose was excreted into bile of normal Wistar rats, hepatobiliary excretion decreased to 7.9% in TR(-) rats within 2 h after intravenous application. This decrease was not due to reduced cellular DMP uptake, as shown by normal expression of Oatp1b2 in livers of TR(-) rats and functional DMP uptake into isolated TR(-) rat hepatocytes. Tissue concentrations of phalloidin were also not altered in any of the transgenic mice. Interestingly, the decrease of biliary DMP excretion in the TR(-) rats was not followed by any increase of phalloidin accumulation in the liver but yielded a compensatory excretion of the toxin into urine, indicating that hepatocytes of TR(-) rats expelled phalloidin back into blood circulation.
Gavrilova
Olga
O
Institute of Pharmacology and Toxicology, Justus Liebig University of Giessen, Frankfurter Str. 107, D-35392 Giessen, Germany.
Geyer
Joachim
J
Petzinger
Ernst
E
D000470:Alkaloids / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000545:Amanita / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D000470:Alkaloids; C412617:KLHL1 protein, human; D008840:Microfilament Proteins; C000880:desmethylphalloin