The Peroxidative Activation of Butylated Hydroxytoluene to BHT-Quinone Methide and Stilbenequinone
Butylated hydroxytoluene (BHT, 2,6-di-tert-butyl-4-methyl-phenol) is a commonly used antioxidant allowed in foods in amounts up to 0.02% of the weight of fat present. BHT helps prevent undesirable oxidation reactions from occurring by acting as a free radical scavenger. BHT is also used as a stabilizer in pesticides, gasolines and lubricants, soaps and cosmetics, and as an antiskinning agent in paints and inks (1). BHT has been shown to have a protective effect against the toxicity and carcinogenicity of a wide variety of chemicals (2). However, several recent animal studies have questioned the presumed safety of this antioxidant. For example, BHT has been shown to cause lung damage in mice (3,4), hemorrhagic death in rats (5) and can act as a tumor promoter in both mice and rats (6,7). One of the best characterized toxic effects of BHT is the destruction of type I alveolar and pulmonary endothelial cells (8) in the mouse lung. This lung damage is thought to arise from the biotransformation of BHT into BHT-quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone) (9,10), a highly reactive compound (see Figure 1). BHT has been demonstrated to be metabolized to BHT-quinone methide in vivo in the mouse (10) and rat (11). This reaction is presumably catalyzed by a cytochrome P-450 related enzyme (12,13). As a class of chemical compounds, quinone methides have been shown to react with cellular nucleophiles including amines, carbohydrates, alcohols, thiols, and olefins (14).
KeywordsCovalent Binding Butylate Hydroxy Toluene Microsomal Protein Butylate Hydroxyanisole Peroxidase Enzyme
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- 1.Clinical Toxicology of Commercial Products, 5th Ed., R.E. Gosselin, R.P. Smith and H.C. Hodge, eds., Williams and Wilkins, Baltimore (1984).Google Scholar
- 6.H.P. Witschi, Enhancement of lung tumor formation in mice, in: “Carcinogenesis”, M.J. Mass, et al., eds., Raven Press, New York (1985).Google Scholar
- 7.K. Imaida, S. Fukushima, T. Shirai, T. Masui, T. Ogiso and N. Ito, Promoting activities of butylated hydroxyanisole, butylated hydroxytoluene and sodium L-ascorbate on forestomach and urinary bladder carcinogenesis initiated with methylnitrosourea in F344 male rats, Gann 75: 769 (1984).PubMedGoogle Scholar
- 15.L.J. Marnett and T.E. Eling, Cooxidation during prostaglandin biosynthesis: A pathway for the metabolic activation of xenobiotics, in: “Reviews in Biochemical Toxicology, 5,”, E. Hodgson and J.R. Bond, eds., Elsevier Biomedical, New York (1983).Google Scholar
- 16.S.M. Cohen, T.V. Zenser, G. Muraski, S. Fukushima, M.B. Mattammal, N.S. Rapp and B.B. Davis, Aspirin inhibition of N-(4-[5-nitro-2-furyl]-2thiazolyl)formamide-induced lesions of the urinary bladder correlated with inhibition of metabolism by bladder prostaglandin endoperoxide synthetase, Cancer Res. 41: 3355 (1981).PubMedGoogle Scholar