Effects of cyclosporin on kidney glutathione metabolism and cytochrome P-450 in the rabbit: possible implication of eicosanoid metabolism.
This study was designed to assess Cyclosporin A (CsA) nephrotoxicity in the rabbit-possibly a more sensitive species than the rat-and to explore the mechanism of this toxicity with special attention to glutathione metabolism disturbances and cytochrome P-450 level in the kidney. CsA given for three days at a daily dose of 50 mg/kg (s.c.) induced nephrotoxicity as assessed by histological abnormalities and by a significant increase in blood urea nitrogen and urinary enzyme activities: N-acetyl-beta-D-glucosaminidase and L-gamma-glutamyl-transferase. This observed renal injury was of the same order as that obtained in the rat. In addition, there was a significant increase in oxidized glutathione content (40%) while reduced glutathione level remained unchanged. Concurrently, there was a significant decrease in renal cortex glutathione reductase (49%) and to a lesser extent in glutathione peroxidase activities (16%) whereas that of glutathione-S-transferase was not modified. A significant increase in renal cortex cytochrome P-450 (3-fold versus controls) was also observed. The mechanism of CsA nephrotoxicity is to be related to a cytochrome P-450 induction. This event could induce the observed impairments in renal glutathione metabolism and Na+K(+)-ATPase activity, via a possible increase in eicosanoid metabolism.
Massicot
F
F
Laboratoire de Toxicologie (E.A. 207), Faculté de Pharmacie, Paris, France.
Thevenin
M
M
Martin
C
C
Warnet
J M
JM
Dutertre-Catella
H
H
Claude
J R
JR
D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D015777:Eicosanoids / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D011817:Rabbits
D015777:Eicosanoids; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione