UP-REGULATION OF GLUTATHIONE SYNTHESIS IN RAT-KIDNEY BY METHYL MERCURY - RELATIONSHIP TO MERCURY-INDUCED OXIDATIVE STRESS
UP-REGULATION OF GLUTATHIONE SYNTHESIS IN RAT-KIDNEY BY METHYL MERCURY - RELATIONSHIP TO MERCURY-INDUCED OXIDATIVE STRESS
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DOI：
10.1016/0006-2952(95)02075-6
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发表时间：
1995-11-09
影响因子：
5.8
通讯作者：
ELLIS, ME
中科院分区：
文献类型：
--
作者：
WOODS, JS;ELLIS, ME
大鼠长期暴露在甲基氢氧化汞(MMH)中，在暴露的初始阶段，肾皮质以Hg2+的形式迅速积累汞，并显著增加氧化应激，其特征是肾脏线粒体形成硫代巴比妥酸反应物质(TREAT)的速度。伴随这些事件的是编码谷氨酰半胱氨酸合成酶(GCS)的mRNA的稳态水平逐渐增加，GCS是谷胱甘肽(GSH)合成的限速酶，肾脏皮质GSH水平增加2-3倍。目前的研究表明，GSH含量的增加伴随着泪水形成速度的下降。在这些初始阶段事件之后，持续的MMH暴露的特征是肾脏Hg2+积累速率平衡，泪液形成率和GCS mRNA水平急剧下降，但肾脏皮质GSH含量持续上升。泪液形成率下降后用丁硫氨酸亚磺胺消耗GSH并不会导致泪液形成率的反弹。这些结果表明，MMH暴露初期的氧化应激源于CH3Hg2+向Hg2+的转化，而Hg2+又通过上调肾脏GCS mRNA的表达来诱导Hg2+和/或氧化剂清除GSH分子的合成。研究结果还表明，对Hg2+介导的氧化应激的抵抗可能与GSH合成上调的能力更密切相关，而不是与GSH水平本身的升高密切相关。
Prolonged exposure of rats to methyl mercury hydroxide (MMH) results, during the initial phase of exposure, in the rapid accumulation of mercury as Hg2+ by kidney cortex and in a significant increase in oxidative stress, as characterized by the rate of formation of thiobarbituric acid reactive substances (TEARS) by renal mitochondria. These events are accompanied by a progressive increase in steady-state levels of the mRNA encoding gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in glutathione (GSH) synthesis and a 2- to 3-fold elevation in renal cortical GSH levels. The present study showed that the increase in GSH content was accompanied by a concomitant decrease in the rate of TEARS formation. Subsequent to these initial phase events, continued MMH exposure was characterized by equilibration in the rate of renal Hg2+ accumulation, a sharp decrease in both the TEARS formation rate and GCS mRNA level, but sustained elevation of renal cortical GSH content. Depletion of GSH with buthionine sulfoximine subsequent to the decline in the rate of TEARS formation did not result in a rebound of the TEARS formation rate. These findings suggest that oxidative stress during the initial phase of MMH exposure is derived from the transformation of CH3Hg+ to Hg2+, which, in turn, induces the synthesis of Hg2+- and/or oxidant-scavenging GSH molecules via the up-regulation of renal GCS mRNA. The findings also suggest that resistance to Hg2+-mediated oxidative stress may be more closely associated with the capacity for up-regulation of GSH synthesis than with elevated GSH levels per se.