Nomura F, Ohnishi K, Koen H, Iida S, Tanabe Y, Hatano H, Okuda K
Hepatology. 1985 Nov-Dec;5(6):1190-3. doi: 10.1002/hep.1840050621.
To evaluate the effects of anaerobic conditions and inducers for the mixed-function oxidase system on the metabolism of mitomycin C, a bioreductive alkylating agent widely used for the treatment of hepatocellular carcinoma, experiments so designed were performed in rats and mice. Metabolism of mitomycin C by microsomes from normal rat liver and diethyl-nitrosamine-induced mouse hepatocellular carcinoma tissue was assessed from the disappearance of the quinone portion of mitomycin C and by measurement of alkylating metabolites using 4-(p-nitrobenzyl)pyridine as a trapping agent. The metabolism of mitomycin C measured by the two independent methods was strikingly increased under anaerobic conditions in both intact and tumor tissues. Since involvement of cytochrome P-450 in the metabolic activation of mitomycin C was shown recently, effects of representative inducers for the mixed-function oxidase system on the metabolism of mitomycin C were also studied. Phenobarbital treatment resulted in a significant increase in the metabolism of mitomycin C in both intact and tumor tissues under anaerobic conditions. The markedly enhanced formation of active metabolites of mitomycin C under anaerobic conditions may explain on a metabolic basis, at least in part, our recent clinical observations that chemoembolizations with microcapsular forms of mitomycin C is more effective than conventional bolus administration of this agent in the treatment of hepatocellular carcinoma. Combination of anaerobic conditions and induction of the mixed-function oxidase system may be applicable to chemotherapy of hepatic malignancy.
为评估厌氧条件及混合功能氧化酶系统诱导剂对丝裂霉素C代谢的影响，丝裂霉素C是一种广泛用于治疗肝细胞癌的生物还原烷基化剂，我们在大鼠和小鼠身上进行了如此设计的实验。通过丝裂霉素C醌部分的消失以及使用4-(对硝基苄基)吡啶作为捕获剂测量烷基化代谢产物，评估正常大鼠肝脏微粒体和二乙基亚硝胺诱导的小鼠肝细胞癌组织微粒体对丝裂霉素C的代谢。在完整组织和肿瘤组织中，通过这两种独立方法测量的丝裂霉素C代谢在厌氧条件下均显著增加。由于最近已表明细胞色素P-450参与丝裂霉素C的代谢活化，因此还研究了混合功能氧化酶系统代表性诱导剂对丝裂霉素C代谢的影响。苯巴比妥处理导致在厌氧条件下完整组织和肿瘤组织中丝裂霉素C的代谢均显著增加。厌氧条件下丝裂霉素C活性代谢产物形成的显著增强至少在一定程度上可以从代谢角度解释我们最近的临床观察结果，即微囊化形式的丝裂霉素C化疗栓塞在治疗肝细胞癌方面比该药物的传统推注给药更有效。厌氧条件与混合功能氧化酶系统诱导的联合应用可能适用于肝脏恶性肿瘤的化疗。
