Impaired biliary excretion and whole body elimination of methylmercury in rats with congenital defect in biliary glutathione excretion.
Biliary excretion of methylmercury, a major route of elimination of this toxic compound, was less than 2% of control in Eisai hyperbilirubinemic (EHBR) rats, a mutant Sprague-Dawley strain with a defect in biliary excretion of a variety of organic anions, including glutathione S-conjugates and reduced glutathione (GSH). Biliary GSH excretion in EHBR rats was also < 2% of controls, confirming previous findings. Impaired biliary methylmercury and GSH excretion was not explained by decreased hepatic content of these compounds. Indeed, hepatic methylmercury and GSH concentrations in EHBR rats were actually double those of controls. To assess the significance of the impaired biliary excretion in the whole body elimination of the toxicant, 203Hg excretion was measured over a 17-day period after intraperitoneal administration of either 0.5 or 5 mumol/kg of 203Hg-methylmercury chloride. The results for the two doses were similar. Methylmercury was eliminated by a first order process; however, the biological half-line was significantly longer in the EHBR rats, 46 to 54 days versus 18 to 22 days. Fecal excretion was the main route of elimination in both control and mutant animals. At necropsy (17 days), 16% to 25% of the 203Hg dose was recovered in the liver of the EHBR rats, whereas livers of control animals contained less than 2%of the administered dose. These findings demonstrate the biliary excretion of methylmercury is markedly impaired in EHBR rats and is associated with a low biliary GSH excretion, providing support for the hypothesis that methylmercury is normally transported across the canalicular membrane by a GSH-dependent mechanism, and presumably as a GSH mercaptide (CH3Hg-SG).(ABSTRACT TRUNCATED AT 250 WORDS)
Ballatori
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Department of Environmental Medicine, University of Rochester School of Medicine, NY 14642, USA.
Gatmaitan
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Truong
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AT
D000818:Animals; D001646:Bile / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006207:Half-Life; D006932:Hyperbilirubinemia / Q000235:genetics / Q000378:metabolism*; D008631:Mercury Radioisotopes; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D008767:Methylmercury Compounds / Q000493:pharmacokinetics*; D009154:Mutation; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D012636:Secretory Rate / Q000235:genetics
D008631:Mercury Radioisotopes; D008767:Methylmercury Compounds; D005978:Glutathione