Gurtoo H L, Hipkens J H, Sharma S D
Cancer Res. 1981 Sep;41(9 Pt 1):3584-91.
The role of glutathione in the biological effects of cyclophosphamide (CP) was evaluated by investigating the following: effect of CP on hepatic glutathione levels; relationship between hepatic glutathione depletion (repletion) and the binding of [chloroethyl-3H]CP and [4-14C]CP to hepatic macromolecules; effects of interaction between CP (or acrolein) and diethyl maleate (a classical glutathione depletor), and/or between CP and cysteine on the binding of labeled CP to hepatic macromolecules, on the induction of hematuria, on the content of hepatic cytochrome P-450, on weight gain in rats, on survival in mice, and on the chemotherapeutic efficacy of CP against Walker 256 carcinoma in rats. CP and acrolein produced dose-dependent depletion of hepatic glutathione in mice, whereas phosphoramide mustard was at least one order of magnitude less effective. Acrolein caused death in mice; CP became covalently bound to hepatic macromolecules, prevented weight gain in rats, and produced hematuria and depression of hepatic cytochrome P-450 in vivo. These effects of CP (or acrolein) were enhanced by diethyl maleate but partially blocked by cysteine. On the other hand, reduction in the volume of Walker 256 carcinoma in rats by CP was not antagonized by cysteine. All these investigations point to the following conclusions: (a) acrolein produced during the metabolism of CP binds to proteins and, by doing so may denature these proteins; and (b) acrolein in vivo preferentially reacts with glutathione, and sulfhydryl-containing compounds may protect against acrolein toxicity and at the same time not interfere with the chemotherapeutic activity of CP.
通过研究以下方面评估了谷胱甘肽在环磷酰胺（CP）生物学效应中的作用：CP对肝脏谷胱甘肽水平的影响；肝脏谷胱甘肽耗竭（补充）与[氯乙基 - 3H]CP和[4 - 14C]CP与肝脏大分子结合之间的关系；CP（或丙烯醛）与马来酸二乙酯（一种经典的谷胱甘肽耗竭剂）之间以及CP与半胱氨酸之间的相互作用对标记CP与肝脏大分子结合、血尿诱导、肝脏细胞色素P - 450含量、大鼠体重增加、小鼠存活以及CP对大鼠Walker 256癌化疗疗效的影响。CP和丙烯醛在小鼠中产生了剂量依赖性的肝脏谷胱甘肽耗竭，而磷酰胺芥的效力至少低一个数量级。丙烯醛导致小鼠死亡；CP与肝脏大分子共价结合，阻止大鼠体重增加，并在体内产生血尿和肝脏细胞色素P - 450降低。CP（或丙烯醛）的这些作用被马来酸二乙酯增强，但被半胱氨酸部分阻断。另一方面，CP对大鼠Walker 256癌体积的减小未被半胱氨酸拮抗。所有这些研究得出以下结论：（a）CP代谢过程中产生的丙烯醛与蛋白质结合，这样做可能使这些蛋白质变性；（b）体内的丙烯醛优先与谷胱甘肽反应，含巯基化合物可预防丙烯醛毒性，同时不干扰CP的化疗活性。
