Differential effects of cyclosporin on hepatic and renal heme, cytochrome P-450 and drug metabolism. Possible role in nephrotoxicity of the drug.
Treatment of rats with 25 or 50 mg/kg cyclosporin A for 6 days elicited vastly different responses in hepatic and renal heme and drug metabolism activities. In the liver, cytochrome P-450 concentration was decreased significantly (to 70-75% of the control). This was accompanied by a marked reduction in benzo[a]pyrene hydroxylase activity (to 20-28% of the control). Aniline hydroxylation was also decreased, but to a lesser extent (to 77% of the control). In contrast, in the kidney cytochrome P-450 concentration was significantly increased to (145-170% of the control), along with a modest decrease in benzo[a]pyrene hydroxylation activity. In this organ, the concentration of porphyrins was severely decreased (to 30% of the control). Also, the activities of delta-aminolevulinate (ALA) synthetase and ALA dehydratase, as well as that of heme oxygenase, were inhibited. It is suggested that in the kidney the inhibition of degradation, rather than an enhanced rate of synthesis of the heme molecule, contributes to the observed increase in cytochrome P-450 concentration. In the liver, the decrease in the cytochrome concentration could not be explained in terms of an alteration in the rate of heme biosynthesis or degradation. Therefore, the observed decrease in cytochrome P-450 concentration could reflect the direct inactivation of the hemoprotein or regulation of apoprotein production by cyclosporin and/or its metabolite(s). The possible relevance of the observations to cyclosporin nephrotoxicity is discussed.
Mayer
R D
RD
Department of Urology, University of Rochester School of Medicine, NY 14642.
Berman
S
S
Cockett
A T
AT
Maines
M D
MD
D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D003524:Cyclosporins; D065607:Cytochrome P-450 Enzyme Inhibitors; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D000815:Aniline Hydroxylase; D001579:Benzopyrene Hydroxylase; D006419:Heme Oxygenase (Decyclizing); D009251:NADPH-Ferrihemoprotein Reductase