Mayer R D, Maines M D
Department of Urology, University of Rochester School of Medicine, NY 14642.
Biochem Pharmacol. 1990 May 15;39(10):1565-71. doi: 10.1016/0006-2952(90)90522-m.
We have examined the toxicity of trans-platinum (trans-diamminedichloroplatinum II) to heme and hemoprotein metabolism in the kidney of glutathione (GSH)-depleted rats and compared it with that produced by cis-platinum. Unlike cis-platinum treatment (7.0 mg/kg, i.v.) which caused after 7 days significant increases in cytochromes P450 and b5, and a marked decrease in porphyrin content of the kidney, trans-platinum alone (7 mg/kg, i.v.) did not elicit notable changes in these variables when measured 1 or 7 days after treatment. Also, cis-platinum treatment significantly altered the heme degradation pathway by increasing the activity of heme oxygenase and decreasing that of biliverdin reductase; trans-platinum treatment did not elicit a response in these activities. However, when rats were given the inhibitor of GSH synthesis, D,L-buthionine-S,R-sulfoximine (BSO), the subsequent administration (2 hr later) of trans-platinum produced, in 1 day, the spectrum of responses that were mediated by cis-platinum after 7 days. In the kidneys of rats treated with BSO plus trans-platinum the concentration of platinum measured only about 50% of that detected in the kidneys of rats treated with trans-platinum alone. In the liver, trans-platinum by itself or in combination with BSO was ineffective in altering the measured variables of heme metabolism. The possibility that similarity between cis-platinum and trans-platinum plus BSO may extend to systems other than heme metabolism, e.g. GSH synthesis and degradation, was examined. cis-Platinum caused significant inhibition of both renal gamma-glutamyl synthetase and gamma-glutamyl transpeptidase after 7 days, but not after 1 day. Twenty-four hours after treatment, BSO + trans-platinum caused inhibition of gamma-glutamylcysteine synthetase activity, whereas this activity in animals treated with BSO alone had returned to control values. At this time point, neither oxidized glutathione (GSSG)-reductase nor gamma-glutamyl transpeptidase activity was affected by trans-platinum + BSO treatment. The findings suggest that GSH constitutes an important defense mechanism against trans-platinum alteration of heme metabolism and may play a role in cellular accumulation of the drug in an inactive complex. It is proposed that BSO treatment, despite resulting in a diminished intracellular concentration of trans-platinum, allows reaction of the metal complex with target molecules by virtue of its ability to deplete GSH.
我们研究了反式铂（反式二氨二氯铂II）对谷胱甘肽（GSH）耗竭大鼠肾脏中血红素和血红蛋白代谢的毒性，并将其与顺式铂产生的毒性进行了比较。与顺式铂治疗（7.0mg/kg，静脉注射）不同，顺式铂治疗7天后导致细胞色素P450和b5显著增加，肾脏卟啉含量显著降低，单独使用反式铂（7mg/kg，静脉注射）在治疗后1天或7天测量时，这些变量没有明显变化。此外，顺式铂治疗通过增加血红素加氧酶的活性和降低胆绿素还原酶的活性，显著改变了血红素降解途径；反式铂治疗在这些活性方面没有引起反应。然而，当给大鼠注射GSH合成抑制剂D，L-丁硫氨酸-S，R-亚砜亚胺（BSO）时，随后（2小时后）注射反式铂在1天内产生了顺式铂7天后介导的一系列反应。在接受BSO加反式铂治疗的大鼠肾脏中，测得的铂浓度仅约为单独接受反式铂治疗的大鼠肾脏中检测到浓度的50%。在肝脏中，反式铂单独使用或与BSO联合使用在改变血红素代谢的测量变量方面无效。研究了顺式铂与反式铂加BSO之间的相似性是否可能扩展到血红素代谢以外的系统，例如GSH合成和降解。顺式铂在7天后导致肾γ-谷氨酰合成酶和γ-谷氨酰转肽酶显著抑制，但在1天后没有。治疗24小时后，BSO +反式铂导致γ-谷氨酰半胱氨酸合成酶活性受到抑制，而单独用BSO治疗的动物中该活性已恢复到对照值。在这个时间点，反式铂+ BSO治疗对氧化型谷胱甘肽（GSSG）还原酶和γ-谷氨酰转肽酶活性均无影响。这些发现表明，GSH构成了对抗反式铂改变血红素代谢的重要防御机制，并且可能在药物以无活性复合物形式在细胞内积累中起作用。有人提出，BSO治疗尽管导致细胞内反式铂浓度降低，但由于其耗尽GSH的能力，使金属复合物能够与靶分子反应。
