The antioxidant butylated hydroxytoluene induces apoptosis in human U937 cells: the role of hydrogen peroxide and altered redox state.
Exposure of U937 cells to the antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT), unlike exposure to other antioxidants such as N,N'-diphenyl-1,4-phenylenediamine, Trolox or alpha-tocopherol, promotes a time- and concentration-dependent induction of apoptosis. This response was prevented by the iron chelator o-phenanthroline and by the thiol reagent N-acetylcysteine but was increased remarkably in cells pre-exposed to the catalase inhibitor 3-amino-1,2,4-triazole or to L-buthionine-[S,R]-sulfoximine, a specific inhibitor of glutathione synthesis. Furthermore, the BHT-induced apoptotic response was markedly enhanced by cytochrome P450 inhibitors. Taken together, the experimental results presented in this study indicate that BHT efficiently induces apoptosis in U937 cells and that this response is not caused by products of cytochrome P450 metabolism. Instead, apoptosis appeared to be causally linked to an altered cellular redox state in which hydrogen peroxide plays a pivotal role.
Palomba
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Istituto di Farmacologia e Farmacognosia, Università di Urbino, Italy.
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D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002084:Butylated Hydroxytoluene / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D053938:DNA Fragmentation; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004587:Electrophoresis, Agar Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers; D006035:Glycyrrhiza; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D010084:Oxidation-Reduction; D029596:Paeonia; D010618:Phenanthrolines / Q000494:pharmacology; D020298:U937 Cells
D000975:Antioxidants; D065607:Cytochrome P-450 Enzyme Inhibitors; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D010618:Phenanthrolines; C038462:shakuyaku-kanzoh-toh; D002084:Butylated Hydroxytoluene; D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide; D002374:Catalase; C025205:1,10-phenanthroline; D000111:Acetylcysteine; D008797:Metyrapone