Paper
Noninhibitory effect of antioxidants ethoxyquin, 2(3)-tert-butyl-4-hydroxyanisole and 3,5-di-tert-butyl-4-hydroxytoluene on hepatic peroxisome proliferation and peroxisomal fatty acid beta-oxidation induced by a hypolipidemic agent in rats.
Published Apr 1, 1983 · N. Lalwani, M. Reddy, S. Qureshi
Cancer research
25
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Abstract
6-Ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin) and the phenolic antioxidants 2(3)- tert -butyl-4-hydroxyanisole and 3,5-di- tert -butyl-4-hydroxytoluene inhibit the development of tumors induced by several chemical carcinogens that are genotoxic. The antioxidants appear to exert these protective effects by inhibiting metabolic activation and by enhancing enzyme systems that facilitate the detoxification of electrophilic form(s) of carcinogens. Information regarding the protective effects, if any, of antioxidants against carcinogenesis by chemical carcinogens that do not appear to generate electrophilic or mutagenic metabolites is, however, lacking. To examine the proposal that the carcinogenicity of such nonmutagenic compounds is due to their ability to initiate lipid peroxidation chain reactions either directly or indirectly, we plan to systematically investigate the effects of antioxidants on hepatocarcinogenesis by peroxisome proliferators. We have studied the acute effects of antioxidants ethoxyquin, 2(3)- tert -butyl-4-hydroxyanisole, and 3,5-di- tert -butyl-4-hydroxytoluene on the induction, in the rat liver, of hepatic peroxisome proliferation and peroxisome-associated enzymes by 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methyl propionic acid (ciprofibrate), a potent peroxisome proliferator. Ethoxyquin at 0.5% (w/w) dietary level exerted no inhibitory effect on the induction by ciprofibrate (0.1%, w/w) of hepatomegaly, peroxisome proliferation (volume and numerical density), catalase, carnitine acetyltransferase, heat-labile peroxisomal enoyl-coenzyme A hydratase, and peroxisomal fatty acid β-oxidation system. Both 2(3)- tert -butyl-4-hydroxyanisole (0.7%, w/w) and 3,5-di- tert -butyl-4-hydroxytoluene (0.7 or 0.07%) also failed to inhibit the ciprofibrate-induced hepatomegaly and hepatic peroxisome proliferation. Additionally, none of these antioxidants altered the ciprofibrate-induced increase in M r 80,000 peroxisome proliferation-associated polypeptide in liver as analyzed by sodium dodecyl sulfate:polyacrylamide gel electrophoresis. The similar increases in peroxisome population and elevations of H2O2-producing peroxisomal fatty acid β-oxidation system suggest that excess levels of intracellular H2O2 are generated in the livers of rats fed ciprofibrate either alone or in combination with a dietary antioxidant. These experiments provide a model system to test the hypothesis that peroxisome proliferator carcinogenesis is mediated by H2O2 and that antioxidants by inhibiting lipid peroxidation could retard or inhibit this process.
Non-RCT
Animal StudyAntioxidants ethoxyquin, 2(3)-tert-butyl-4-hydroxyanisole, and 3,5-di-tert-butyl-4-hydroxytoluene show no inhibitory effect on hepatocarcinogenesis induced by nonmutagenic compounds like cipr
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