Li S, Thompson S A, Kavanagh T J, Woods J S
Department of Environmental Health, School of Public Health and Community Medicine, University of Washington, Seattle 98195, USA.
Toxicol Appl Pharmacol. 1996 Nov;141(1):59-67. doi: 10.1006/taap.1996.0260.
In previous studies we reported that prolonged treatment of rats with subtoxic levels of mercury as methylmercury hydroxide (MMH) elicited a two- to threefold increase in renal glutathione (GSH) content and a three- to fourfold increase in the mRNA encoding the catalytically active heavy subunit of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis. In the present studies, we demonstrate that enhanced expression of GCS mRNA and GSH synthesis rapidly occur following acute MMH treatment and, moreover, that increased expression of renal GCS mRNA is localized predominantly to regions of the kidney cortex consistent with the principal distribution of mercury in the kidney. Previous studies have demonstrated that resistance to mercury toxicity during prolonged MMH exposure may be associated with the ability to up-regulate GSH synthesis subsequent to intracellular dealkylation of MMH to Hg2+. The present finding that GCS mRNA and GSH levels are rapidly increased in kidney cells which are most susceptible to mercury toxicity supports the view that up-regulation of GSH synthesis occurs as an initial adaptive response to Hg2(+)-mediated cytotoxicity following acute as well as prolonged mercury exposure.
在先前的研究中，我们报道用亚毒性水平的汞（以氢氧化甲基汞（MMH）形式）对大鼠进行长期处理，会使肾脏谷胱甘肽（GSH）含量增加两到三倍，并且编码γ-谷氨酰半胱氨酸合成酶（GCS）催化活性重亚基的mRNA增加三到四倍，GCS是GSH合成中的限速酶。在本研究中，我们证明急性MMH处理后，GCS mRNA的表达增强和GSH合成迅速发生，此外，肾脏GCS mRNA表达的增加主要定位于肾皮质区域，这与汞在肾脏中的主要分布一致。先前的研究表明，在长期MMH暴露期间对汞毒性的抗性可能与MMH在细胞内脱烷基化为Hg2+后上调GSH合成的能力有关。目前的发现，即GCS mRNA和GSH水平在对汞毒性最敏感的肾细胞中迅速增加，支持了这样一种观点，即GSH合成的上调是急性和长期汞暴露后对Hg2+介导的细胞毒性的一种初始适应性反应。
