TRACE METAL ALTERATION OF RENAL PORPHYRIN METABOLISM

肾脏是许多有毒微量金属的主要靶器官。 目前的证据表明，卟啉尿，一种早期中毒前 长期金属暴露的表现，主要是肾 因此，可以作为一个诊断指标， 肾脏中的金属中毒 在研究甲基 汞（MMH）诱发肾性卟啉尿，3个主要生化事件 似乎是这一过程的基础。 这些措施是： (1)金属诱导的肾脏还原型谷胱甘肽（GSH）含量耗竭，（2） 肾尿卟啉原脱羧酶（UD）受损，和（3） 肾ALA合成酶活性的延迟增加。 据推测 金属诱导的肾GSH耗竭导致失活和/或 抑制UD，导致肾卟啉代谢的原发性阻断。 GSH耗竭也增强血红素催化，导致继发性 ALA合成酶诱导，随后卟啉过量产生。 这些变化表现为卟啉尿症。 建议进行研究，以描述每种药物的确切机制， 这些变化是由MMH诱导的大鼠肾卟啉尿引起的 皮质作为实验模型。 一个高度敏感 将使用这些实验室开发的HPLC荧光分光光度法 定量组织和测定介质中的卟啉，并研究 金属和还原型谷胱甘肽影响肾卟啉代谢的机制。 将使用特定的GSH消耗剂和补充剂来评估 还原型谷胱甘肽与肾血红素相互作用及卟啉调节 长时间接触金属 这些事件与血脂的关系 过氧化和甲醛形成，作为潜在的毒性后遗症， 还将研究肾细胞中金属诱导的GSH耗竭。 拟议的研究将大大增加目前的理解， 血红素和卟啉在肾脏代谢中的调节及作用 GSH在这个过程中 在展示金属 在长时间低水平暴露期间，GSH和血红素调节受损， 这些事件与已知的组织损伤原因的关系， 研究将为理解金属如何 毒性在肾细胞中开始。 有证据表明，卟啉尿症是一种 与微量金属有关的中毒前生化事件的放大 暴露将有助于诊断意义卟啉尿症， 检测和预防慢性金属中毒。

The kidney is a principal target organ for numerous toxic trace metals. Current evidence suggests that porphyrinuria, an early pre-toxic manifestation of prolonged metal exposure, is predominantly of renal origin, and may, therefore, serve as a diagnostic indicator of ensuing metal toxicity in the kidney. In studies on the mechanisms by which methyl mercury (MMH) elicits renal porphyrinuria, 3 principal biochemical events which appear to underlie this process have been identified. These are: (1) metal-induced depletion of renal reduced glutathione (GSH) content, (2) consequent impairment of renal uroporphyrinogen decarboxylase (UD), and (3) a delayed increase in renal ALA synthetase activity. It is hypothesized that metal-induced depletion of renal GSH leads to deactivation and/or inhibition of UD, causing a primary block in renal porphyrin metabolism. GSH depletion also enhances heme catabolism, leading to a secondary induction of ALA synthetase with subsequent porphyrin overproduction. These changes are manifested as porphyrinuria. Studies are proposed to delineate the precise mechanisms by which each of these changes is elicited using MMH-induced porphyrinuria in rat kidney cortex as the experimental model. A highly sensitive HPLC-spectrofluorimetric assay developed in these laboratories will be used to quantitate porphyrins in tissue and assay media and to study the mechanisms of metal and GSH effects on renal porphyrin metabolism. Specific GSH depeting and repleting agents will be used to assess the interaction of GSH with renal heme and porphyrin regulation during prolonged metal exposure. The relationship of these events to lipid peroxidation and formaldehyde formation, as potential toxic sequellae of metal-induced GSH depletion in kidney cells, will also be investigated. The proposed studies will add substantially to the current understanding of the regulation of heme and porphyrin metabolism in the kidney and the role of GSH in this process. In demonstrating the mechanisms by which metals impair GSH and heme regulation during prolonged, low-level exposure, and the relationship of these events to known causes of tissue damage, these studies will provide a biochemical basis for understanding how metal toxicity is initiated in renal cells. Evidence that porphyrinuria is a magnifestation of pre-toxic biochemical events associated with trace metal exposure will lend diagnostic significance to porphyrinuria in the detection and prevention of chronic metal toxicity.