title: Reduction of arginase I activity and manganese levels in the liver during exposure of rats to methylmercury: a possible mechanism.
abstract: 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.
authors.affiliation: Master's Program in Environmental Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Kanda
authors.forename: Daigo
authors.initials: D
authors.lastname: Sumi
authors.forename: Akiko
authors.initials: A
authors.lastname: Endo
authors.forename: Takashi
authors.initials: T
authors.lastname: Toyama
authors.forename: Cheng-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Makoto
authors.initials: M
authors.lastname: Kikushima
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
mesh_terms: D000818:Animals; D001119:Arginase / Q000187:drug effects* / Q000378:metabolism; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000378:metabolism*; D008767:Methylmercury Compounds / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D008767:Methylmercury Compounds; D013438:Sulfhydryl Compounds; D008345:Manganese; D001119:Arginase; C004925:methylmercuric chloride