Stimulation of Microsomal Drug Oxidation in Liver and Kidney of Rats Treated with the Oncolytic Agent cis-Dichlorodiammineplatinum-II

Litterst, Charles L.; Tong, Samuel; Hirokata, Y; Siddik, Zahid H.

doi:10.1159/000137768

Cited by 15 publications

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“…The tissue-specific toxicity of cis-platinum to the kidney is well documented (Blachley & Hill, 1981;Litterst et al, 1983). The present results show that cis-platinum treatment also elicits vastly different responses in the liver and the kidney haem-metabolism activities and in the activities of the y-glutamyl-cycle enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…Renal toxicity, however, constitutes a major limiting factor in the clinical use ofthis co-ordinated platinum complex (Blachley & Hill, 1981). Moreover, in the kidney, cis-platinum has been shown to cause a pronounced increase in concentration of the microsomal haem and cytochrome P-450 (Litterst et al, 1983;Jollie & Maines, 1985). Indeed, the magnitude of increase in concentration of the cytochrome in the kidney surpasses that elicited by most other agents (Jollie & Maines, 1985;Litterst et al, 1975).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, the magnitude of increase in concentration of the cytochrome in the kidney surpasses that elicited by most other agents (Jollie & Maines, 1985;Litterst et al, 1975). On the other hand, the concentration of the haemoprotein in the liver is refractory to cis-platinum treatment (Litterst et al, 1975(Litterst et al, , 1983). In the kidney, cis-platinum also causes perturbations in activities of various enzymes of haem-metabolism pathway (Jollie & Maines, 1985) and has been reported to cause alterations in GSH concentration (Litterst et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

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Differential effect of cis-platinum (cis-diamminedichloroplatinum) on regulation of liver and kidney haem and haemoprotein metabolism. Possible involvement of γ-glutamyl-cycle enzymes

Maines¹

1986

Biochemical Journal

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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.

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Section: Discussionmentioning

confidence: 99%