The effects of cisplatin on the concentration of protein thiols and glutathione in the rat kidney.
The effect of a nephrotoxic dose of cisplatin (5 mg/kg) on the concentrations in the rat kidney of both glutathione and protein-bound thiols was investigated. Total glutathione and oxidised glutathione were measured in the cortex and outer medulla using specific enzyme-based assays. The high-molecular-weight thiols were quantified in cells of the proximal tubule using a cyto-chemical technique. The concentration of total glutathione (oxidised and reduced) in the kidney cortex and outer medulla was significantly higher than that of controls at 1 h following cisplatin administration. The amount by which the concentration in treated animals exceeded that in controls increased to 50% at 72 h and remained significantly elevated for 120 h following treatment. This increase was mainly attributable to an increase in the concentration of reduced glutathione. In contrast, the concentration of protein thiols in the proximal tubules decreased significantly at 8 h after dosing, reaching a nadir 29% below that of controls at 120 h, thus coinciding with the maximal functional disturbance in the kidney as reflected by the concentration of blood urea. The decrease in protein thiols could not be correlated stoichiometrically with the platinum concentration in the cortex and outer medulla, which reached a peak of 16.3 +/- 0.3 micrograms/g wet tissue at 72 h after treatment. Evidently cisplatin perturbs the equilibrium that is said to exist between the concentration of reduced glutathione and that of protein thiols. This perturbation occurs well before the onset of overt functional disturbance of the kidney and is evident before the point at which the damage to the kidney caused by cisplatin becomes irreversible.
Mistry
P
P
Biology and Biochemistry Department, Brunel University, Uxbridge, Middlesex, UK.
Merazga
Y
Y
Spargo
D J
DJ
Riley
P A
PA
McBrien
D C
DC
D000818:Animals; D002945:Cisplatin / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D010984:Platinum / Q000032:analysis / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013438:Sulfhydryl Compounds / Q000032:analysis / Q000378:metabolism*; D013997:Time Factors
D013438:Sulfhydryl Compounds; D010984:Platinum; D005978:Glutathione; D002945:Cisplatin