Biliary secretion of glutathione and of glutathione-metal complexes

As bile is the main route of elimination of many metals, a large number of studies have been directed toward the characterization of the hepatobiliary transport of both endogenous and exogenous metals. Although some progress has been made, we still know little of the basic mechanisms involved in the hepatocellular uptake of metals, in their intracellular translocation and metabolism, or in their transport into bile. Our recent studies have focused on the last step in the hepatobiliary transport of mercury, namely, the secretion of the metal from liver cells into bile. The rate of secretion of methyl and inorganic mercury into bile was low in suckling rats and rapidly increased to adult rates soon after weaning. These changes closely followed similar developmental changes in the biliary secretion of reduced glutathione (GSH). When GSH secretion into bile was completely inhibited, without changing hepatic levels of GSH or mercury, mercury secretion was also completely blocked. Mercury secretion paralleled individual and sex-related differences in GSH secretion. At the same time, the secretion of mercury was independent of bile flow, of the thiol and mercury concentration gradients between bile and liver cells, and of those between bile and plasma. Our results, therefore, indicate a close coupling between the secretion of mercury and that of GSH. These in vivo findings, along with in vitro studies by others in vesicles isolated from the canalicular membrane of the liver cell, indicate a carrier-mediated transport system for GSH, but the nature of the linkage of this transport system with mercury secretion is not yet fully established. Our data and those in the literature are consistent with the involvement of at least two steps in the movement of mercury from liver cells to bile--the formation of a mercury-glutathione complex in the liver cell, followed by the secretion of this complex through a process closely linked to GSH secretion. The identification of GSH as an endogenous complexing agent in the transport of metals between tissues and body fluids now permits the design of therapeutic strategies aimed at exploiting this transport vehicle to effect the removal of metals via physiological routes of excretion. The present discussion considers the role of GSH in the hepatobiliary transport of metals. In doing so, a brief review is given of current understanding of hepatic GSH metabolism and transport.