Massicot F, Thevenin M, Martin C, Warnet J M, Dutertre-Catella H, Claude J R
Laboratoire de Toxicologie (E.A. 207), Faculté de Pharmacie, Paris, France.
Drug Chem Toxicol. 1994 Nov;17(4):449-62. doi: 10.3109/01480549409014311.
This study was designed to assess Cyclosporin A (CsA) nephrotoxicity in the rabbit-possibly a more sensitive species than the rat-and to explore the mechanism of this toxicity with special attention to glutathione metabolism disturbances and cytochrome P-450 level in the kidney. CsA given for three days at a daily dose of 50 mg/kg (s.c.) induced nephrotoxicity as assessed by histological abnormalities and by a significant increase in blood urea nitrogen and urinary enzyme activities: N-acetyl-beta-D-glucosaminidase and L-gamma-glutamyl-transferase. This observed renal injury was of the same order as that obtained in the rat. In addition, there was a significant increase in oxidized glutathione content (40%) while reduced glutathione level remained unchanged. Concurrently, there was a significant decrease in renal cortex glutathione reductase (49%) and to a lesser extent in glutathione peroxidase activities (16%) whereas that of glutathione-S-transferase was not modified. A significant increase in renal cortex cytochrome P-450 (3-fold versus controls) was also observed. The mechanism of CsA nephrotoxicity is to be related to a cytochrome P-450 induction. This event could induce the observed impairments in renal glutathione metabolism and Na+K(+)-ATPase activity, via a possible increase in eicosanoid metabolism.
本研究旨在评估环孢素A（CsA）对家兔的肾毒性（家兔可能比大鼠对其更为敏感），并探讨这种毒性的机制，特别关注肾脏中谷胱甘肽代谢紊乱和细胞色素P - 450水平。以每日50mg/kg的剂量皮下注射CsA，连续给药三天，通过组织学异常以及血尿素氮和尿酶活性（N - 乙酰 - β - D - 氨基葡萄糖苷酶和L - γ - 谷氨酰转移酶）的显著升高来评估，结果显示其诱导了肾毒性。观察到的肾损伤程度与在大鼠中所获得的损伤程度相当。此外，氧化型谷胱甘肽含量显著增加（40%），而还原型谷胱甘肽水平保持不变。同时，肾皮质谷胱甘肽还原酶活性显著降低（49%），谷胱甘肽过氧化物酶活性降低程度较小（16%），而谷胱甘肽 - S - 转移酶活性未发生改变。还观察到肾皮质细胞色素P - 450显著增加（相较于对照组增加了3倍）。CsA肾毒性的机制可能与细胞色素P - 450的诱导有关。这一事件可能通过类花生酸代谢的可能增加，导致观察到的肾脏谷胱甘肽代谢和Na + K(+) - ATP酶活性受损。
