Wei H, Qiu L, Divine K K, Ashbaugh M D, McIntyre L C, Fernando Q, Gandolfi A J
Department of Pharmacology and Toxicology, University of Arizona, Tucson 85724-5114, USA.
Drug Chem Toxicol. 1999 May;22(2):323-41. doi: 10.3109/01480549909017838.
Previous work has suggested that endogenous sulfhydryls, such as glutathione (GSH) and cysteine, are involved in the uptake and toxicity of HgCl2. To study this possibility, uptake and toxicity of synthesized Hg(SG)2, Hg(cysteinylglycine)2 [Hg(CYS-GLY)2] and Hg(CYS)2 were investigated in rabbit renal proximal tubule suspensions (RPT). The intracellular K+ was used as a toxicity indicator, and the mercury content in the tubules was measured by proton induced x-ray emission analysis. The toxicity rank order of the three synthesized mercury-thiol-complexes from the highest to the lowest was: Hg(CYS)2 > Hg(CYS-GLY)2 > Hg(SG)2. However, no significant difference among the mercury contents in the tubules exposed to these synthesized mercury-thiol-complexes was detected. Acivicin (0.25 mM), an inhibitor of gamma-glutamyltranspeptidase (GGT), decreased the toxicity of Hg(SG)2 in a manner that did not decrease the uptake of mercury in the tubules. This suggests that the toxicity of Hg(SG)2 requires processing to Hg(CYS-GLY)2 or Hg(CYS)2, while Hg(SG)2 may be taken up by the tubules via Na(+)-dependent GSH transporter since 10 mM acivicin, an inhibitor of this transporter dramatically decreased the uptake of Hg(SG)2. Organic anion transporter plays a minor role, if any, in the toxicity and uptake of Hg(SG)2 and Hg(CYS)2 since p-aminohippuric acid (PAH), an inhibitor of organic anion transporter, did not have significant effect on their uptake and toxicity. L-phenylalanine, an inhibitor of the neutral amino acid decreased the uptake of mercury, but to a lesser extent. This suggested that neutral amino acid transporter seemed to play a role, in part, in the toxicity and uptake of synthesized Hg(CYS)2. In summary, the data suggested that basolateral transport is important for the toxicity of the three synthesized mercury-thiol-complexes, and a variety of mechanisms are involved in the toxicity and uptake of these complexes in isolated rabbit RPT.
先前的研究表明，内源性巯基，如谷胱甘肽（GSH）和半胱氨酸，参与了HgCl2的摄取和毒性作用。为了研究这种可能性，我们在兔肾近端小管悬浮液（RPT）中研究了合成的Hg(SG)2、Hg(半胱氨酰甘氨酸)2 [Hg(CYS-GLY)2]和Hg(CYS)2的摄取和毒性。细胞内K+用作毒性指标，通过质子诱导X射线发射分析测量小管中的汞含量。三种合成的汞硫醇络合物的毒性顺序从高到低为：Hg(CYS)2 > Hg(CYS-GLY)2 > Hg(SG)2。然而，在暴露于这些合成的汞硫醇络合物的小管中，未检测到汞含量有显著差异。阿西维辛（0.25 mM），一种γ-谷氨酰转肽酶（GGT）抑制剂，以不降低小管中汞摄取的方式降低了Hg(SG)2的毒性。这表明Hg(SG)2的毒性需要加工成Hg(CYS-GLY)2或Hg(CYS)2，而Hg(SG)2可能通过Na(+)-依赖性GSH转运体被小管摄取，因为10 mM阿西维辛，这种转运体的抑制剂显著降低了Hg(SG)2的摄取。有机阴离子转运体在Hg(SG)2和Hg(CYS)2的毒性和摄取中起的作用较小，如果有的话，因为对氨基马尿酸（PAH），一种有机阴离子转运体抑制剂，对它们的摄取和毒性没有显著影响。L-苯丙氨酸，一种中性氨基酸抑制剂，降低了汞的摄取，但程度较小。这表明中性氨基酸转运体似乎在一定程度上参与了合成的Hg(CYS)2的毒性和摄取。总之，数据表明基底外侧转运对三种合成的汞硫醇络合物的毒性很重要，并且多种机制参与了这些络合物在分离的兔RPT中的毒性和摄取。
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