Rao M S, Lalwani N D, Watanabe T K, Reddy J K
Cancer Res. 1984 Mar;44(3):1072-6.
The objective of this study was to test the hypothesis that hepatocarcinogenesis by peroxisome proliferators, a novel class of chemical carcinogens, is mediated either directly by carcinogenic H2O2, generated by peroxisomal oxidase(s) or indirectly by free radicals produced from H2O2, and that antioxidants could retard or inhibit neoplasia by scavenging active oxygen (super-oxide radicals O(2), hydrogen peroxide, hydroxyl radicals HO, and singlet oxygen 1O2). Accordingly, the effect of synthetic antioxidants 2(3)-tert-butyl-14-hydroxyanisole and ethoxyquin on the peroxisome proliferator 2-[4-(2,2-dichlorocyclopropyl)phenoxy]2-methyl-propionic acid (ciprofibrate)-induced hepatic tumorigenesis has been examined in male Fischer 344 rats. Rats were fed either a 2(3)-tert-butyl-4-hydroxyanisole (0.5% w/w)- or ethoxyquin (0.5% w/w)-containing diet with or without ciprofibrate (10 mg/kg of body weight) for 60 weeks. Rats fed ciprofibrate (10 mg/kg of body weight) in the diet or fed a diet with no added chemicals served as controls. Results of this study demonstrated that ethoxyquin markedly inhibited the hepatic tumorigenic effect of ciprofibrate, as evidenced by a decreased incidence of tumors, a decreased number of tumors per liver, and a reduced tumor size. 2(3)-tert-Butyl-4-hydroxyanisole also caused a significant decrease in the incidence and number of hepatocellular carcinomas that were larger than 5 mm. The present data suggest that the inhibitory effect of antioxidants on ciprofibrate-induced hepatic tumorigenesis may be due to H2O2 and free radical-scavenging property of ethoxyquin and 2(3)-tert-butyl-4-hydroxyanisole, since these antioxidants do not prevent peroxisome proliferation and induction of H2O2-generating peroxisomal enzymes in livers of rats fed ciprofibrate. Whether the inhibitory effect of antioxidants is exercised on the presumptive H2O2 initiation process and/or on the postinitiation growth phase of foci and nodules in liver is, at present, unknown.
过氧化物酶体增殖剂是一类新型化学致癌物，其诱发肝癌的过程要么由过氧化物酶体氧化酶产生的致癌性过氧化氢直接介导，要么由过氧化氢产生的自由基间接介导；抗氧化剂可通过清除活性氧（超氧阴离子自由基O₂、过氧化氢、羟基自由基HO和单线态氧¹O₂）来延缓或抑制肿瘤形成。因此，在雄性Fischer 344大鼠中研究了合成抗氧化剂2(3)-叔丁基-4-羟基茴香醚和乙氧喹对过氧化物酶体增殖剂2-[4-(2,2-二氯环丙基)苯氧基]2-甲基丙酸（环丙贝特）诱导的肝脏肿瘤发生的影响。给大鼠喂食含2(3)-叔丁基-4-羟基茴香醚（0.5% w/w）或乙氧喹（0.5% w/w）的饲料，饲料中添加或不添加环丙贝特（10 mg/kg体重），持续60周。喂食含环丙贝特（10 mg/kg体重）的饲料或喂食不添加化学物质的饲料的大鼠作为对照。本研究结果表明，乙氧喹显著抑制了环丙贝特的肝脏致癌作用，表现为肿瘤发生率降低、每只肝脏的肿瘤数量减少以及肿瘤大小减小。2(3)-叔丁基-4-羟基茴香醚也使大于5 mm的肝细胞癌的发生率和数量显著降低。目前的数据表明，抗氧化剂对环丙贝特诱导的肝脏肿瘤发生的抑制作用可能归因于乙氧喹和2(3)-叔丁基-4-羟基茴香醚的过氧化氢和自由基清除特性，因为这些抗氧化剂并不能阻止喂食环丙贝特的大鼠肝脏中的过氧化物酶体增殖和产生过氧化氢的过氧化物酶体酶的诱导。目前尚不清楚抗氧化剂的抑制作用是作用于假定的过氧化氢启动过程和/或肝脏中病灶和结节的启动后生长阶段。
