Mechanisms of hepatic methylmercury uptake

The mechanism by which methylmercury is cleared from hepatic portal blood was examined in isolated rat livers perfused single-pass with Krebs-Henseleit buffer. [203Hg]Methylmercury (0.24-24 microM) was infused over a 30-min interval, followed by a 30-min washout, as a complex with the endogenous ligands L-cysteine (CH3Hg-L-cys), glutathione (CH3Hg-SG), and serum albumin (CH3Hg-albumin), or as a complex with dithiothreitol (CH3Hg-DTT), chloride (CH3HgCl), and the D-enantiomer of cysteine (CH3Hg-D-cys). The sulfhydryl-containing compounds were added at a 10-fold molar excess. When administered as the albumin complex, only a small fraction of the [203Hg]methylmercury was cleared from perfusate (approximately 8%) and excreted into bile (0.7%). Hepatic uptake and biliary excretion of methylmercury was considerably higher for the other complexes: The percent of the dose recovered in liver tissue and bile was, respectively, CH3Hg-albumin, 6.9 and 0.7; CH3Hg-L-cys, 15.7 and 2.3; CH3Hg-D-cys, 27.1 and 2.8; CH3Hg-SG, 17.7 and 2.1; CH3HgCl, 66.5 and 3.2; and CH3Hg-DTT, 70.1 and 19.8. For the dithiothreitol complex, hepatic extraction of methylmercury was nearly complete during single-pass perfusion. A comparison of hepatic removal of increasing doses of CH3Hg-L-cys and CH3Hg-D-cys revealed little difference in uptake between these two enantiomers. Moreover, the fraction of methylmercury removed was similar when infused at concentrations of 0.24, 2.4, and 24 microM, indicating no saturability of uptake within this dose range. Methylmercury was not hepatotoxic at concentrations up to 24 microM if administered as a mercaptide; however, the chloride complex (CH3HgCl) produced cholestasis and an increase in perfusion pressure at a concentration of only 0.24 microM. These findings indicate that hepatic methylmercury uptake and toxicity are dependent on the chemical form in blood plasma. Uptake was faster when methylmercury was present as a cysteine or glutathione complex, as compared to the albumin complex; however, the lack of stereoselectivity indicates that the uptake process may be relatively unselective.