Evidence that alterations in renal metabolism and lipid peroxidation may contribute to cyclosporine nephrotoxicity.
This study was designed to investigate aspects of renal xenobiotic metabolism and the renal cellular response to drug-induced injury, in mediating cyclosporine nephrotoxicity. The relation between CsA and renal enzyme activity has not previously been investigated. In this study, CsA induced alterations in rat renal cortical microsomal NADPH cytochrome P-450 reductase activity, microsomal and mitochondrial lipid peroxidation, and renal cortical glutathione levels were investigated. CsA, in vivo (50 mg/kg/day for 4 days), increased in vitro lipid peroxidation in microsomes and mitochondria. CsA produced a significant uncompetitive inhibition of renal NADPH cytochrome P-450 reductase activity. The low activity and maximal enzyme velocity (Vmax) suggest that the amount of renal enzyme available for metabolism may be a rate-limiting step and could contribute to the development of toxicity. CsA in vivo reduced the renal cortical glutathione ratio (GSH/GSSG), which may also reduce the renal cellular response to CsA injury. This study has demonstrated that CsA nephrotoxicity may, in part, be mediated by CsA-induced alterations in renal xenobiotic metabolism.
Walker
R J
RJ
Department of Renal Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
Lazzaro
V A
VA
Duggin
G G
GG
Horvath
J S
JS
Tiller
D J
DJ
D000818:Animals; D003524:Cyclosporins / Q000633:toxicity*; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism; D007700:Kinetics; D015227:Lipid Peroxidation; D008099:Liver / Q000201:enzymology; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism
D003524:Cyclosporins; D009251:NADPH-Ferrihemoprotein Reductase; D005978:Glutathione