Influence of N-acetylcysteine on the antitumor activity of doxorubicin.
Influence of N-acetylcysteine on the antitumor activity of doxorubicin.
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N-乙酰半胱氨酸对阿霉素抗肿瘤活性的影响。
DOI：
10.5555/uri:pii:0093775483900623
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发表时间：
1983
影响因子：
4
通讯作者：
R. Boerth
中科院分区：
文献类型：
--
作者：
R. Olson;W. E. Stroo;R. Boerth
多柔比星诱导的心肌病自10年前被发现以来，已引起相当大的关注。虽然阿霉素（DOX）产生心脏毒性的机制尚不清楚，但有证据表明，它与药物代谢过程中形成的自由基的作用有关（图1）。Handa和Sate* 最初表明，微粒体NADPH氧化酶系统中的DOX代谢产生超氧阴离子（0;;）。Goodman和Hochstein 3证明，在DOX 1的还原-氧化循环中，醌形式的分子可以循环为半醌，然后多次回到醌形式，以产生超氧阴离子分子并引发脂质过氧化。当Bachur等人4证明大鼠心脏微粒体能够支持DOX产生自由基时，表明自由基氧化机制可能介导该药物的心脏毒性。这一概念得到了Myers等人的数据的支持。Olson等6证明抗氧化剂维生素E和自由基清除剂半胱胺减弱了DOX在小鼠中的急性心脏毒性。谷胱甘肽过氧化物酶途径（图2）通过将过氧化物还原为醇来解毒潜在的破坏性过氧化物，也被证明是DOX诱导的心脏毒性的重要调节剂。马来酸二乙酯对内源性谷胱甘肽的消耗。以及通过减少内源性硒储存（硒是谷胱甘肽过氧化物酶活性所需的辅因子）来抑制谷胱甘肽过氧化物酶显著增强实验动物中DOX诱导的心脏毒性。此外，用马来酸二乙酯预处理兔以将内源性心脏谷胱甘肽水平降低至低于基础值的30%显著增强了DOX在从预处理兔获得的离体乳头肌中的负性变力活性。此外，N-乙酰半胱氨酸（NAC）的研究表明，该药物可显著预防DOX诱导的心脏毒性。“,”
C ONSIDERABLE ATTENTION has been given to doxorubicin-induced cardiomyopathy since its recognition nearly 10 yr ago. Although the mechanism by which doxorubicin (DOX) produces cardiotoxicity is unknown, evidence suggests that it is linked to the effect of free radicals formed during the drug’s metabolism’ (Fig. 1). Handa and Sate* initially showed that DOX metabolism in a microsomal NADPH oxidase system yielded superoxide anion (0;;). Goodman and Hochstein3 demonstrated that, in the reduction-oxidation cycle of DOX 1 molecule in the quinone form could cycle to a semiquinone then back to the quinone form many times to generate molecules of superoxide anion and initiate lipid peroxidation. When Bachur et aL4 demonstrated that heart microsomes from rats were capable of supporting the generation of free radicals from DOX, it was suggested that a free radical oxidative mechanism might mediate the cardiotoxicity of this drug. This concept was supported by data from Myers et al.’ and Olson et al.6 demonstrating that the antioxidant vitamin E and the free radical scavenger cysteamine attenuated the acute cardiotoxicity of DOX in mice. The glutathione peroxidase pathway (Fig. 2), which detoxifies potentially damaging peroxides by reducing them to alcohols, also was shown to be an important modulator of DOX-induced cardiotoxicity.‘.’ Depletion of endogenous glutathione by diethyl maleate’.’ and inhibition of glutathione peroxidase by reduction of endogenous selenium stores (selenium is a required cofactor of glutathione peroxidase activity)‘dramatically potentiated DOX-induced cardiotoxicity in laboratory animals. Furthermore, pretreatment of rabbits with diethyl maleate to lower endogenous cardiac glutathione levels to less than 30% of basal values significantly potentiated the negative inotropic activity of DOX in isolated papillary muscles obtained from pretreated rabbits.’ Additionally, studies with Nacetylcysteine (NAC) have shown this agent to provide significant protection against DOXinduced cardiotoxicity.“,”
谷胱甘肽和可溶性巯基对阿霉素毒性的调节作用。
DOI：
--
发表时间：
1980
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Olson,RD;MacDonald,JS;vanBoxtel,CJ;Boerth,RC;Harbison,RD;Slonim,AE;Freeman,RW;Oates,JA
通讯作者：
Oates,JA