PREVENTION OF DOXORUBICIN CARDIAC TOXICITY IN THE MOUSE BY N-ACETYLCYSTEINE
PREVENTION OF DOXORUBICIN CARDIAC TOXICITY IN THE MOUSE BY N-ACETYLCYSTEINE
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DOI：
10.1172/jci110328
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发表时间：
1981-01-01
影响因子：
15.9
通讯作者：
MYERS, CE
中科院分区：
文献类型：
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作者：
DOROSHOW, JH;LOCKER, GY;MYERS, CE
本研究旨在探讨外源性SH化合物对小鼠阿霉素（一种心脏毒性抗肿瘤药物）毒性的影响。在阿霉素（20 mg/kg, ig）前1 h给予n -乙酰-1-半胱氨酸药理学剂量（2000 mg/kg）预处理CDF1小鼠，死亡率从100% （n = 44）降至37.7% (n = 53), P < 0.001。不同时间和剂量的n-乙酰半胱氨酸显著降低其保护活性。n-乙酰半胱氨酸预处理也显著降低了接受多剂量阿霉素的动物的长期死亡率；每隔2周给药3次阿霉素（5 mg/kg, ig）第3次10周后，n-乙酰半胱氨酸预处理组的存活率为51.4% (n= 35)，而阿霉素预处理前生理盐水组的存活率为16.7% (n= 30), P < 0.01。在本实验中，n-乙酰半胱氨酸预处理与生理盐水预处理相比，还能使阿霉素相关的总重和心脏湿重损失分别减少55.2% （P < 0.05）和60.9% （P < 0.02）。n -乙酰半胱氨酸预处理也消除了阿霉素心肌病的EM证据，但没有减轻其对肝脏或小肠粘膜毒性作用的形态学特征。n-乙酰半胱氨酸的心脏保护作用可以部分解释为429 +-。n-乙酰半胱氨酸给药1 h后，心肌非蛋白SH含量增加60% (P < 0.01)；同时肝内非蛋白SH浓度与对照组差异不显著。n-乙酰半胱氨酸治疗也使P388白血病[小鼠]细胞的非蛋白SH含量增加近3倍；然而，它并没有改变阿霉素对这种小鼠肿瘤的化疗活性。虽然n-乙酰半胱氨酸阻断了阿霉素的心脏毒性，但它不影响阿霉素在心脏或肝脏中的摄取或代谢。这些结果提示，心脏游离SH群的浓度可能在阿霉素心脏毒性的发展中起作用，用n-乙酰半胱氨酸增加心脏非蛋白SH群的含量可能是提高阿霉素化疗指数的一种手段。
This study was undertaken to investigate the effect of exogenous SH compound administration on the toxicity of doxorubicin [a cardiotoxic antitumor agent] in mice. Pretreatment of CDF1 mice with a pharmacologic dose (2000 mg/kg) of N-acetyl-1-cysteine 1 h beore doxorubicin (20 mg/kg, i.p.) decreased lethality from 100% n = 44) to 37.7% (n = 53), P < 0.001. Variation in the timing and dose of n-acetylcysteine significantly diminished its protective activity. Pretreatment with n-acetylcysteine also significantly reduced long-term mortality in animals receiving multiple doses of doxorubicin; 10 wk after the 3rd of 3 doxorubicin doses (5 mg/kg, i.p.) administered at 2-wk intervals, survival in th n-acetylcysteine pretreated group was 51.4% (n= 35) compared with 16.7% (n = 30) for animals receiving saline before doxorubicin, P < 0.01. In this experiment, n-acetylcysteine pretreatment also diminished doxorubicin-related losses in total body weight and heart wet weight by 55.2% (P < 0.05) and 60.9% (P < 0.02), respectively, compared with animals pretreated with saline. N-acetylcysteine pretreatment also ablated EM evidence of doxorubicin cardiomyopathy without alleviating morphological features of its toxic effects on the liver or small intestinal mucosa. The cardioprotective action of n-acetylcysteine may be paratially explained by the 429 .+-. 60% increase in cardiac nonprotein SH content (P < 0.01) that was measured 1 h after n-acetylcysteine administration; nonprotein SH concentration in the liver at the same time was insignificantly different from control levels. Treatment with n-acetylcysteine also increased the nonprotein SH ccontent of P388 leukemia [mouse] cells nearly 3-fold; however, it did not alter the chemotherapeutic activity of doxorubicin against this murine tumor. Whereas n-acetylcysteine blocked doxorubicin cardiac toxicity, it did not affect the uptake or metabolism of doxorubicin in the heart or liver. These results suggest that the concentration of free SH groups in the heart may play a role in the development of doxorubicin cardiac toxicity and that augmenting cardiac nonprotein SH group content with n-acetylcysteine may provide a means to enhanced the chemotherapeutic index of doxorubicin.