Maines M D
Biochem J. 1986 Aug 1;237(3):713-21. doi: 10.1042/bj2370713.
The treatment of rats with cis-platinum (cis-diamminedichloroplatinum) for 1, 3 or 7 days elicited vastly different responses in the liver and the kidney in activities of enzymes of haem-metabolism pathway and gamma-glutamyl-cycle enzymes. The differences resided in the magnitude, direction and the time course of responses. In general, the liver was by far less severely affected, and when a response was elicited, it displayed an earlier onset (1-3 days), with a return to normal at 7 days. In the kidney, however, the effects were notable after 3 days of treatment, and became more pronounced at 7 days. Specifically, the activity of 5-aminolaevulinic acid (ALA) synthetase and contents of cytochrome P-450 and the microsomal haem were decreased in the liver. In contrast, in the kidney, cytochrome P-450 and haem concentrations were significantly increased, with no change in ALA synthetase activity. The increase in the kidney haem content appeared to reflect an increased formation of haem, as suggested by the elevated activity of ferrochelatase and the concomitant decrease in tissue porphyrin levels. In the kidney, a time-dependent and pronounced inhibition of activities of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione production, and gamma-glutamyl transpeptidase, the first enzyme in glutathione breakdown, were observed. The enzyme activities, 7 days after treatment, were only 40 and 60% of the control values respectively. In contrast, these enzyme activities were not affected in the liver. Complexing cis-platinum with cysteine considerably intensified the entire spectrum of effects of cis-platinum in the kidney. Notably, cytochrome P-450 concentration and haem oxygenase activity were increased to about 3.5 and 6 times the control values, respectively. gamma-Glutamylcysteine synthetase activity was decreased to less than 20% of the control. It is suggested that the differential effectiveness of cis-platinum in the liver and the kidney in alternating haem metabolism is related to the vast differences which exist between these organs in the activities of gamma-glutamyl-cycle enzymes. It is further suggested that this may promote the formation in the kidney, but not in the liver, of a cis-platinum-cysteine complex that is more stable, and thus biologically more effective, than the parent compound.
用顺铂（顺二氨二氯铂）对大鼠进行1天、3天或7天的处理，在血红素代谢途径的酶和γ-谷氨酰循环酶的活性方面，肝脏和肾脏产生了截然不同的反应。差异存在于反应的幅度、方向和时间进程中。总体而言，肝脏受影响的程度要小得多，一旦产生反应，其发作时间较早（1 - 3天），并在7天时恢复正常。然而，在肾脏中，处理3天后效应明显，7天时变得更加显著。具体而言，肝脏中5-氨基酮戊酸（ALA）合成酶的活性、细胞色素P-450的含量和微粒体血红素均降低。相反，在肾脏中，细胞色素P-450和血红素浓度显著增加，而ALA合成酶活性没有变化。肾脏中血红素含量的增加似乎反映了血红素形成的增加，这可由亚铁螯合酶活性的升高以及组织卟啉水平的相应降低所表明。在肾脏中，观察到γ-谷氨酰半胱氨酸合成酶（谷胱甘肽产生中的限速酶）和γ-谷氨酰转肽酶（谷胱甘肽分解中的首个酶）的活性呈现时间依赖性且明显受到抑制。处理7天后，这些酶的活性分别仅为对照值的40%和60%。相比之下，这些酶的活性在肝脏中未受影响。将顺铂与半胱氨酸络合极大地增强了顺铂在肾脏中的整个效应谱。值得注意的是，细胞色素P-450浓度和血红素加氧酶活性分别增加到对照值的约3.5倍和6倍。γ-谷氨酰半胱氨酸合成酶活性降低到对照值的不到20%。有人提出，顺铂在肝脏和肾脏中对血红素代谢的不同作用效果与这些器官在γ-谷氨酰循环酶活性方面存在的巨大差异有关。进一步表明，这可能促进在肾脏而非肝脏中形成一种比母体化合物更稳定、因而在生物学上更有效的顺铂 - 半胱氨酸复合物。
