The effect of silibinin on experimental cyclosporine nephrotoxicity.
The immunosuppressive drug cyclosporine A (CsA), is metabolized by cytochrome P-450 IIIA. It causes acute reversible as well as chronic largely irreversible nephrotoxic effects. This effect is bases on vasoconstriction of the afferent and efferent glomerular arterioles which leads to a reduction in glomerular plasma flow and glomerular filtration rate. The mechanisms of the vasoconstriction are unclear with a number of different pathways under discussion. Silibinin is the main constituent of silymarin. Silibinin inhibits lipid peroxidation on hepatic microsomes and mitochondria of rats and is also able to reduce the activity of various monooxygenases. Cyclosporin-induced lipid peroxidation and affected cytochrome P-450 may even contribute to cyclosporine nephrotoxicity. We examined the possibility that silibinin had a protective effect as a result of its radical scavenging properties. Silibinin, 5 mg/kg BW i.p., was administered 30 min before cyclosporine application at dose of 30 mg/kg BW daily i.p. The biochemical parameters, total malondialdehyde (MDA) in whole blood and kidney homogenates and specific content of cytochrome P-450 in microsomal liver suspension were estimated. Three groups were studied: controls (con), cyclosporine alone (CsA), and cyclosporine plus silibinin (CsA + Sili). Creatinine was significantly increased after 2 weeks in both cyclosporine treated groups compared to controls (CsA 60.2 +/- 10.6 versus 45.8 +/- 10.4 mumol/L, p < 0.05; and CsA + Sili 72.0 +/- 8.3 versus 45.8 +/- 10.4 mumol/L, p < 0.001) and glomerular filtration rate (GFR) was significantly decreased (p < 0.0001) in the same groups. Total MDA was elevated only in CsA rats (2.26 +/- 0.35 mumol/L, p < 0.05) in comparison with controls (1.60 +/- 0.44 mumol/L, p < 0.05) and with rats treated by CsA + Sili (1.65 +/- 0.27 mumol/L, p < 0.05). The specific content of cytochrome P-450 in microsomal liver suspension was increased in group CsA + Sili (1.179 +/- 0.115 nmol/mg prot) compared to control group (0.775 +/- 0.086 nmol/mg prot., p < 0.05) and also CsA group (0.806 +/- 0.098 nmol/mg prot., p < 0.05). In conclusion, silibinin decreased cyclosporine-induced lipid peroxidation without a protective effect on GFR. These data indicate that this pathway is not be important in cyclosporine-induced nephrotoxicity. Administration of both drugs (CsA + sili) increased the specific content of cytochrome P-450 in liver microsomes. This suggests that the effect of silibinin on cyclosporine biotransformation in the liver is via cytochrome P-450.
Zima
T
T
1st Institute of Medical Chemistry and Biochemistry, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Kameníková
L
L
Janebová
M
M
Buchar
E
E
Crkovská
J
J
Tesar
V
V
D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008315:Malondialdehyde / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012838:Silymarin / Q000494:pharmacology*
D016166:Free Radical Scavengers; D007166:Immunosuppressive Agents; D012838:Silymarin; D008315:Malondialdehyde; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System