Suzuki S, Oka T, Ohkuma S, Kuriyama K
Transplantation. 1987 Sep;44(3):363-8. doi: 10.1097/00007890-198709000-00008.
Biochemical mechanisms underlying cyclosporine (CsA)-induced nephrotoxicity and the effect of concomitant administration of prednisolone (Pr) on the nephrotoxicity were studied. Male Wistar rats were treated with the vehicles used for CsA and Pr administration (group 1), Pr alone (group 2), CsA alone (group 3), or CsA plus Pr (group 4), respectively. The dose of CsA was 5 mg/kg/day, i.p. for the initial 7 days, and was decreased to 2.5 mg/kg/day i.p. thereafter. The dose of Pr was always maintained at one-tenth of that of CsA. At 10, 30, and 90 days after the initiation of these treatments, blood urea nitrogen (BUN) and serum levels of creatinine and CsA were determined. The syntheses of DNA, RNA, and protein, Na+, K+-adenosine triphosphate (ATP)ase activity, and ATP content were measured using homogenates of the renal cortex obtained from each experimental group. At an early stage (at 10 and 30 days) of CsA administration, the impairment of renal function and inhibition of the synthesis of DNA and RNA appeared in groups 3 and 4. The magnitude of these changes was found to be greater in group 3 (CsA alone) than in group 4 (CsA plus Pr). Group 3 also showed a significant reduction of Na+, K+-ATPase activity as well as ultrastructural abnormalities. At a later stage (at 90 days), however, such differences in nephrotoxicity between groups 3 and 4 were not detected. These results strongly suggest that inhibition of the synthesis of DNA and RNA and the activity of enzymes related to the functions of cell membrane, such as Na+, K+-ATPase, may be involved in the occurrence of CsA-induced nephrotoxicity. The present results also suggest that the concomitant administration of Pr with CsA may reduce the nephrotoxicity of CsA at early stages of CsA administration, but this preventive effect of Pr may disappear if the administration of CsA is prolonged.
研究了环孢素（CsA）诱导肾毒性的生化机制以及泼尼松龙（Pr）联合给药对肾毒性的影响。将雄性Wistar大鼠分别用用于CsA和Pr给药的赋形剂处理（第1组）、单独用Pr处理（第2组）、单独用CsA处理（第3组）或CsA加Pr处理（第4组）。CsA的剂量为5mg/kg/天，腹腔注射，最初7天给药，此后降至2.5mg/kg/天腹腔注射。Pr的剂量始终维持在CsA剂量的十分之一。在这些处理开始后的10天、30天和90天，测定血尿素氮（BUN）以及肌酐和CsA的血清水平。使用从每个实验组获得的肾皮质匀浆测量DNA、RNA和蛋白质的合成、Na +、K + -三磷酸腺苷（ATP）酶活性以及ATP含量。在CsA给药的早期阶段（10天和30天），第3组和第4组出现肾功能损害以及DNA和RNA合成抑制。发现这些变化的程度在第3组（单独使用CsA）中比在第4组（CsA加Pr）中更大。第3组还显示Na +、K + -ATP酶活性显著降低以及超微结构异常。然而，在后期阶段（90天），未检测到第3组和第4组之间在肾毒性方面的此类差异。这些结果强烈表明，DNA和RNA合成的抑制以及与细胞膜功能相关的酶（如Na +、K + -ATP酶）的活性可能参与了CsA诱导的肾毒性的发生。目前的结果还表明，Pr与CsA联合给药可能在CsA给药的早期阶段降低CsA的肾毒性，但如果CsA给药时间延长，Pr的这种预防作用可能会消失。
