The toxicity of methylmercury (MeHg) is, in part, thought to be due to its interaction with thiol groups in a variety of enzymes, but the molecular targets of MeHg are poorly understood. Arginase I, an abundant manganese (Mn)-binding protein in the liver, requires Mn as an essential element to exhibit maximal enzyme activity. In the present study, we examined the effect of MeHg on hepatic arginase I in vivo and in vitro. Subcutaneous administration of MeHg (10 mg/kg) for 8 days to rats resulted in marked suppression of arginase I activity. With purified arginase I, we found that interaction of MeHg with arginase I caused the aggregation of arginase I as evaluated by centrifugation and subsequent precipitation, and then the reduction of catalytic activity. Experiments with organomercury column confirmed that arginase I has reactive thiols that are covalently bound to organomercury. While MeHg inhibited arginase I activity, Mn ions were released from this enzyme. These results suggest that MeHg-mediated suppression of hepatic arginase I activity in vivo is, at least in part, attributable to covalent modification of MeHg or substantial leakage of Mn ions from the active site.
- Arginase I
- Covalent modification
ASJC Scopus subject areas
- Health, Toxicology and Mutagenesis