Kensler T, Guyton K, Egner P, McCarthy T, Lesko S, Akman S
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA.
Prog Clin Biol Res. 1995;391:103-16.
Many tumor promoters, including the phorbol esters, do not require biotransformation to stimulate cell growth. By contrast, some promoters, notably organic peroxides and hydroperoxides, must be metabolized to reactive intermediates to trigger signal transduction pathways for mitogenesis. These intermediates can be both free radicals and electrophiles. For example, skin tumor promoters such as tert-butyl hydroperoxide, cumene hydroperoxide, dicumyl peroxide and benzoyl peroxide undergo metal-dependent activation in keratinocytes to form alkoxyl, alkyl and aryl radicals as determined by spin trapping and electron paramagnetic resonance spectroscopy. These radicals can participate in substitution, addition or hydrogen-abstraction reactions leading to protein oxidation or alkylation, lipid peroxidation and/or DNA damage. Scavenger studies indicate that these macromolecular interactions mediate the cytotoxic and mitogenic effects of these peroxides. In some instances radicals can undergo further oxidation to electrophiles. The promoting activity of butylated hydroxytoluene hydroperoxide is mediated by a quinone methide, an electrophile formed through a phenoxyl radical intermediate. In this instance, covalent interaction of the quinone methide with sulfhydryl groups or other nucleophiles in the target cell appears to transmit the molecular signal for cell division and replication. Like the phorbol esters, peroxides and hydroperoxides lead to a genetic reprogramming manifest by the induction of immediate early response genes such as c-jun and late response genes such as ornithine decarboxylase, suggesting convergence in the molecular signalling processes among different classes of promoters.
许多肿瘤促进剂，包括佛波酯，不需要生物转化就能刺激细胞生长。相比之下，一些促进剂，特别是有机过氧化物和氢过氧化物，必须代谢为反应性中间体才能触发有丝分裂的信号转导途径。这些中间体可以是自由基和亲电试剂。例如，皮肤肿瘤促进剂，如叔丁基过氧化氢、异丙苯过氧化氢、过氧化二异丙苯和过氧化苯甲酰，在角质形成细胞中经历金属依赖性活化，通过自旋捕获和电子顺磁共振光谱测定，形成烷氧基、烷基和芳基自由基。这些自由基可以参与取代、加成或氢提取反应，导致蛋白质氧化或烷基化、脂质过氧化和/或DNA损伤。清除剂研究表明，这些大分子相互作用介导了这些过氧化物的细胞毒性和促有丝分裂作用。在某些情况下，自由基可以进一步氧化成亲电试剂。叔丁基羟基甲苯过氧化氢的促进活性由醌甲基化物介导，醌甲基化物是通过苯氧基自由基中间体形成的亲电试剂。在这种情况下，醌甲基化物与靶细胞中的巯基或其他亲核试剂的共价相互作用似乎传递了细胞分裂和复制的分子信号。与佛波酯一样，过氧化物和氢过氧化物会导致遗传重编程，表现为诱导立即早期反应基因如c-jun和晚期反应基因如鸟氨酸脱羧酶，这表明不同类别的促进剂在分子信号传导过程中存在趋同。
