Biochemical determinants of Adriamycin toxicity in mouse liver, heart and intestine.
Biochemical determinants of Adriamycin toxicity in mouse liver, heart and intestine.
复制标题
阿霉素对小鼠肝脏、心脏和肠道毒性的生化决定因素。
DOI：
10.1016/0006-2952(92)90250-m
复制
发表时间：
1992
影响因子：
5.8
通讯作者：
Benson,AM
中科院分区：
文献类型：
--
作者：
Odom,AL;Hatwig,CA;Stanley,JS;Benson,AM
在有和没有静脉注射阿霉素（剂量范围23-30 mg/kg）的雌性CD-1小鼠中检查了与肝脏、心脏和肠对急性阿霉素®毒性的不同耐受性相关的生化特征。与心脏和肠不同，肝脏对阿霉素毒性具有相对抗性，具有高水平的谷胱甘肽和谷胱甘肽过氧化物酶，并且在阿霉素后1-3小时内表现出非蛋白硫醇浓度急剧下降，6小时反弹。与阿霉素或其代谢产物的共价结合不能定量解释非蛋白硫醇的损失，这涉及氧化机制。在肝脏中未观察到脂质过氧化，显然是由于有效利用了抗氧化防御。阿霉素导致心脏过氧化脂质显着增加，表明氧化组织损伤，预计会加剧心脏毒性。然而，非蛋白巯基浓度没有减少心脏或肠中的阿霉素。心脏和肠道的谷胱甘肽过氧化物酶活性水平极低，这可能会限制谷胱甘肽的利用，以保护免受氧化毒性。DT黄递酶的活性，这可能有一个激活作用，在阿霉素代谢，是高的心脏和肠，诱导4倍，在肝脏中的阿霉素。
Biochemical characteristics relevant to the differential susceptibilities of liver, heart, and intestine to acute Adriamycin®toxicity were examined in female CD-1 mice with and without intravenous Adriamycin (dose range 23–30 mg/kg). The liver which, unlike heart and intestine, is relatively resistant to Adriamycin toxicity, had high levels of glutathione and glutathione peroxidase, and exhibited a sharp decline in non-protein thiol concentrations within 1–3 hr with rebound by 6hr after Adriamycin. Covalent binding to Adriamycin or its metabolites could not account quantitatively for the loss of non-protein thiols, implicating an oxidative mechanism. No lipid peroxidation was observed in the liver, apparently due to effective utilization of antioxidant defenses. Adriamycin caused significant increases in cardiac lipid peroxides, indicative of oxidative tissue damage, which would be expected to exacerbate cardiotoxicity. However, non-protein thiol concentrations did not decrease in heart or in intestine in response to Adriamycin. Both heart and intestine had extremely low levels of glutathione peroxidase activity, which may limit glutathione utilization for protection against oxidative toxicity. The activity of DT diaphorase, which may have an activating role in Adriamycin metabolism, was high in heart and intestine and was induced 4-fold in liver in response to Adriamycin.