Reduction of arginase I activity and manganese levels in the liver during exposure of rats to methylmercury: a possible mechanism.
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.
Kanda
Hironori
H
Master's Program in Environmental Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Sumi
Daigo
D
Endo
Akiko
A
Toyama
Takashi
T
Chen
Cheng-Liang
CL
Kikushima
Makoto
M
Kumagai
Yoshito
Y
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
D008767:Methylmercury Compounds; D013438:Sulfhydryl Compounds; D008345:Manganese; D001119:Arginase; C004925:methylmercuric chloride