Kanda Hironori, Sumi Daigo, Endo Akiko, Toyama Takashi, Chen Cheng-Liang, Kikushima Makoto, Kumagai Yoshito
Master's Program in Environmental Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Arch Toxicol. 2008 Nov;82(11):803-8. doi: 10.1007/s00204-008-0307-9. Epub 2008 May 17.
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.
甲基汞（MeHg）的毒性部分被认为是由于其与多种酶中的巯基相互作用，但人们对MeHg的分子靶点了解甚少。精氨酸酶I是肝脏中一种丰富的与锰（Mn）结合的蛋白质，需要Mn作为必需元素才能表现出最大的酶活性。在本研究中，我们在体内和体外研究了MeHg对肝脏精氨酸酶I的影响。给大鼠皮下注射MeHg（10 mg/kg）8天导致精氨酸酶I活性显著抑制。对于纯化的精氨酸酶I，我们发现通过离心和随后的沉淀评估，MeHg与精氨酸酶I的相互作用导致精氨酸酶I聚集，进而催化活性降低。用有机汞柱进行的实验证实精氨酸酶I具有与有机汞共价结合的反应性巯基。虽然MeHg抑制精氨酸酶I活性，但Mn离子从该酶中释放出来。这些结果表明，体内MeHg介导的肝脏精氨酸酶I活性抑制至少部分归因于MeHg的共价修饰或Mn离子从活性位点的大量泄漏。
