Impaired biliary excretion and whole body elimination of methylmercury in rats with a congenital defect in biliary glutathione excretion

Abstract

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 μmol/kg of 203Hg-methylmercury chloride. The results for the two doses were similar. Methyhnercury was eliminated by a first order process; however, the biological half-life 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 that 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 (CH 3Hg-SG). This study also provides a direct measure of the contribution of biliary excretion to the whole-body elimination of methylmercury. The biological half-life of the metal was 2.5 times longer in the mutant animals, indicating a critical role for biliary secretion in methyhnercury detoxification.