Role of Glutathione in Mercury Disposition

Abstract

A complex of methylmercury (MeHg) with glutathione (GSH) has been found in several tissues such as brain, liver, erythrocytes and bile. Although the binding of MeHg to GSH is reversible, the complex formation may play an important role in the transport of MeHg.

Species difference in the biliary secretion rate of MeHg reflected total concentration of GSH and its degradation products such as cysteine (Cys) and cysteinylglycine (CysGly) in the bile. It has been reported that hepatic GSH is secreted into bile, and then decomposed enzymatically to CysGly and Cys. These facts suggest that the GSH transport system from liver to bile is one of the determinants of the biliary secretion of MeHg. The main form of MeHg in the bile was found to be MeHg-GSH in mice and hamsters and MeHg-CysGly in rats and guinea pigs. These complexes of MeHg were reabsorbed from the intestine more efficiently than MeHgCl, and transported into the kidneys and liver.

On the other hand, substantial amounts of GSH is released directly from the liver into plasma as a major source of plasma GSH. Specific depletion of hepatic GSH by pretreatment of mice with l,2-dichloro-4-nitrobenzene (DCNB) reduced renal accumulation of MeHg. The renal uptake of MeHg in mice receiving MeHg-GSH intravenously was significantly higher than that in mice receiving MeHgCl. Although MeHg-GSH has hardly been detected in plasma after administration of MeHgCl, our results described above suggest the possibility that the GSH released from the liver into plasma plays an important role in the renal accumulation of MeHg. Inhibition of γ-glutamyltranspeptidase (γ-GTP) by acivicin pretreatment also reduced renal MeHg uptake and increased urinary excretion of MeHg and GSH. These facts indicate that MeHg is transported to the kidney as GSH complex and the MeHg is incorporated into the kidney by a γ-GTP dependent system. Sex and strain differences and developmental changes in the renal uptake of MeHg can at least partially be explained by the difference in renal γ-GTP activity.