Zima T, Kameníková L, Janebová M, Buchar E, Crkovská J, Tesar V
1st Institute of Medical Chemistry and Biochemistry, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Ren Fail. 1998 May;20(3):471-9. doi: 10.3109/08860229809045136.
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.
免疫抑制药物环孢素A（CsA）由细胞色素P - 450 IIIA代谢。它会导致急性可逆以及慢性的、很大程度上不可逆的肾毒性作用。这种作用基于肾小球入球小动脉和出球小动脉的血管收缩，从而导致肾小球血浆流量和肾小球滤过率降低。血管收缩的机制尚不清楚，有多种不同途径正在讨论中。水飞蓟宾是水飞蓟素的主要成分。水飞蓟宾可抑制大鼠肝微粒体和线粒体的脂质过氧化，还能降低各种单加氧酶的活性。环孢素诱导的脂质过氧化以及对细胞色素P - 450的影响甚至可能导致环孢素肾毒性。我们研究了水飞蓟宾因其自由基清除特性而具有保护作用的可能性。在每天腹腔注射剂量为30mg/kg体重的环孢素前30分钟，腹腔注射5mg/kg体重的水飞蓟宾。测定了生化参数，包括全血和肾匀浆中的总丙二醛（MDA）以及微粒体肝悬液中细胞色素P - 450的特定含量。研究了三组：对照组（con）、单独使用环孢素组（CsA）以及环孢素加 水飞蓟宾组（CsA + Sili）。与对照组相比，两个环孢素治疗组在2周后肌酐显著升高（CsA组60.2±10.6对比45.8±10.4μmol/L，p < 0.05；CsA + Sili组72.0±8.3对比45.8±10.4μmol/L，p < 0.001），并且相同组的肾小球滤过率（GFR）显著降低（p < 0.0001）。与对照组（1.60±0.44μmol/L，p < 0.05）以及CsA + Sili治疗组（1.65±0.27μmol/L，p < 0.05）相比，仅CsA大鼠的总MDA升高（2.26±0.35μmol/L，p < 0.05）。与对照组（0.775±0.086nmol/mg蛋白，p < 0.05）以及CsA组（0.806±0.098nmol/mg蛋白，p < 0.05）相比，CsA + Sili组微粒体肝悬液中细胞色素P - 450的特定含量增加（1.179±0.115nmol/mg蛋白）。总之，水飞蓟宾降低了环孢素诱导的脂质过氧化，但对GFR没有保护作用。这些数据表明该途径在环孢素诱导的肾毒性中并不重要。两种药物（CsA + Sili）的联合使用增加了肝微粒体中细胞色素P - 450的特定含量。这表明水飞蓟宾对环孢素在肝脏中生物转化的影响是通过细胞色素P - 450实现的。
