地塞米松的诱导效应对环磷酰胺大鼠毒性的影响

Add-on effects of dexametnasone on cyclophosphamide toxicity in male Wistar rats

目的:观察地塞米松(dexamethasone,DEX)对大鼠细胞色素P450的诱导效应致环磷酰胺(cyclophosphamide,CPA)对肝脏、肾脏、骨髓和膀胱毒性的影响。方法:雄性Wistar大鼠用DEX 50mg·kg^(-1)·d^(-1)诱导4d后,d5分别ip CPA 0,150和200mg·kg^(-1)后36h,观察实验动物肝脏、肾脏、骨髓和膀胱毒性表现。结果:单独DEX诱导具有轻微的肝脏毒性。CPA单次给药造成骨髓细胞G_2/M期细胞的比例稍有升高,出现明显的尿蛋白和尿潜血。DEX的诱导作用增加了CPA的毒性:对肝毒性的增强作用主要表现在血浆ALT升高,肝脏总巯基和蛋白巯基含量降低,肝脏组织肝窦狭窄,肝小叶空泡变性;对肾脏毒性增强表现在血浆BUN和Cr升高,尿液蛋白和潜血增加,肾近端小管变性和髓质出血。DEX和CPA 200mg·kg^(-1)合并用药组骨髓细胞的G_0/G_1期细胞增多,S期细胞明显减少。病理检查表明DEX和CPA合并用药组膀胱发生炎症和出血。结论:DEX诱导后使CPA对大鼠的肾脏、膀胱和骨髓毒性进一步增强,而DEX具有一定的肝脏毒性,与CPA合并给药后肝毒性有增强趋势。

Objective: To study the adjunctive effects of dexamethasone (DEX) on cyclophosphamide (CPA) toxicity in male rats. Methods: Male Wistar rats were ip administered with DEX (0 or 50mg·kg^(-1)) daily for 4 days, and then supplemented with CPA (0, 150 or 200mg·kg^(-1)) on the 5th day. The rats were euthanatized in 36 hours post CPA administration to evaluate toxic manifestations on liver, kidney, bone marrow and bladder of the rats. Results: Single dose of DEX made mild liver toxicity by inducing CYP450. Single dose of CPA resulted in a slight increase of G_2/M myelocytes together with higher incidence of urine protein and occult blood. DEX had add-on effects on CPA liver toxicity, including elevation of plasma ALT, decrease of plasma ALP, reduction of the quantity of total and nonprotein sulfhydryl groups, narrowing of liver sinusoid and vacuolar degeneration of lobules, and on CPA nephrotoxicity, including the escalation of plasma BUN and Cr, elevation of urine protein and occult blood, degeneration of renal proximal tubule and bleeding in medulla. Co-administration of DEX with CPA (200mg·kg^(-1)) increased the myelocytes ratio of G_0/G_1 to S, and with CPA (50mg·kg^(-1)) showed bladder inflammation and bleeding. Conclusion: DEX induction potentiates the hepatotoxicity, nephrotoxicity, myelotoxicity and bladder toxicity of CPA in male rats.