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

Abstract

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.

Cisplatin Nephrotoxicity in Cadmium-Pretreated Rats

“…Therefore, a decrease in the glutathione peroxidase activity could cause accumulation of H20 2 and lipid hydroperoxides, thus leading to deleterious effects. These results correlate well with those of Vernie et al [38] and Milano et al [39] who showed that cisplatin inhibited erythrocyte glutathione peroxidase, and with those re cently published by Hannemann and Baumann [40], Maines [30] did not reveal any effect of cisplatin treat ment on GSH content nor on glutathione reductase activ ity in the kidney. This discrepancy may be explained by the difference in the rat strains used and the treatment regimen (see above).…”

“…They suggest that the mechanism of depletive action of cisplatin on microsomal cytochrome P-450 involves an impairment of the effective assembly of heme and apoprotein moieties. Maines [30] reported an increase in the kidney cyto chrome P-450 7 days after cisplatin treatment. This discrepancy may be explained by the difference in rat strains used and the treatment regimen.…”

“…This discrepancy may be explained by the difference in rat strains used and the treatment regimen. Maines [30] used Sprague-Dawley rats which were treated with a single dose of 9 mg cisplatin/kg and killed 0.25,1,3 and 7 days later. In our study, we used Brown-Norway rats which were injected intraperitoneally (3 mg cisplatin/kg) 3 times at 21-day intervals and killed 3 days after the last injection.…”

Metabolism of Cisplatin to a Nephrotoxin in Proximal Tubule Cells

“…Cisplatin-cysteine-conjugates have been identified in the kidneys of cisplatin-treated rats (25). Maines incubated cysteine and cisplatin in a 2:1 molar ratio for 30 min at 37°C (59). He reported that in the kidney the cysteine-platinum incubation mixture was a more potent inhibitor of hemometabolism and glutathione synthesis than cisplatin.…”

High Pressure Liquid Chromatography and Mass Spectrometry Characterization of the Nephrotoxic Biotransformation Products of Cisplatin

“…Bose and coworkers reported a kinetic analysis of the reaction of cisplatin with cysteine (Bose et al, 1997). Cysteine conjugates of cisplatin have been identified in the kidney (Maines, 1986).…”