The Peroxidative Activation of Butylated Hydroxytoluene to BHT-Quinone Methide and Stilbenequinone

  • David C. Thompson
  • Young Nam Cha
  • Michael A. Trush
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)


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).


Covalent Binding Butylate Hydroxy Toluene Microsomal Protein Butylate Hydroxyanisole Peroxidase Enzyme 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 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
  2. 2.
    H. Babich, Butylated hydroxytoluene (BHT): A review, Environ. Res. 29: 1 (1982).PubMedCrossRefGoogle Scholar
  3. 3.
    A.A. Marino and J.T. Mitchell, Lung damage in mice following intraperitoneal injection of butylated hydroxytoluene, Proc. Soc. Exp. Biol. Med. 140: 122 (1972).PubMedGoogle Scholar
  4. 4.
    H. Witschi and W. Saheb, Stimulation of DNA synthesis in mouse lung following intraperitoneal injection of butylated hydroxytoluene, Proc. Soc. Exp. Biol. Med. 147: 690 (1974).PubMedGoogle Scholar
  5. 5.
    G. Takahashi and K. Kiraga, Dose-response study of hemorrhagic death by dietary butylated hydroxytoluene (BHT) in male rats, Tox. Appl. Pharmacol. 43: 399 (1978).CrossRefGoogle Scholar
  6. 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. 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
  8. 8.
    L.J. Smith, The effect of methylprednisolone on lung injury in mice, J. Lab. Clin. Med. 101: 629 (1983).PubMedGoogle Scholar
  9. 9.
    T. Mizutani, I. Ishida, K. Yamamoto and K. Tajima, Pulmonary toxicity of butylated hydroxytoluene and related alkyl-phenols: Structural requirements for toxic potency in mice, Tox. Appl. Pharmacol. 62: 273 (1982).CrossRefGoogle Scholar
  10. 10.
    T. Mizutani, K. Yamamoto and K. Tajima, Isotope effects on the metabolism and pulmonary toxicity of butylated hydroxytoluene in mice by deuteration of the 4-methyl group, Tox. Appl. Pharmacol. 69: 283 (1983).CrossRefGoogle Scholar
  11. 11.
    Takahashi and K. Hiraga, 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone: A hepatic metabolite of butylated hydroxytoluene in rats, Fd. Cosmet. Toxicol. 17: 451 (1979).CrossRefGoogle Scholar
  12. 12.
    J.P. Kehrer and H. Witschi, Effects of drug metabolism inhibitors on butylated hydroxytoluene-induced pulmonary toxicity in mice, Tox. Appl. Pharmacol. 53: 333 (1980).CrossRefGoogle Scholar
  13. 13.
    K. Tajima, K. Yamamoto and T. Mizutani, Formation of a glutathione conjugate from butylated hydroxytoluene by rat liver microsomes, Biochem. Pharmacol. 34: 2109 (1985).PubMedCrossRefGoogle Scholar
  14. 14.
    A.B. Turner, Quinone methides, Quart. Rev. 18: 347 (1964).CrossRefGoogle Scholar
  15. 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. 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
  17. 17.
    H. Lowry, N.J. Rosebrough, A.L. Farr and R.J. Randall, Protein measurement with the Folin phenol reagent, J. Biol. Chem. 193: 265 (1951).PubMedGoogle Scholar
  18. 18.
    H. Becker, Quinone dehydrogenation. I. The oxidation of monohydric phenols, J. Org. Chem. 30: 982 (1965).CrossRefGoogle Scholar
  19. 19.
    C.D. Cook, N.G. Nash and H.R. Flanagan, Oxidation of hindered phenols. III. The rearrangement of the 2,6-di-t-butyl-4-methylphenoxy radical, J. Amer. Chem. Soc. 77: 1783 (1955).CrossRefGoogle Scholar
  20. 20.
    T. Kurechi and T. Kato, Studies on the antioxidants. XX. The effect of butylated hydroxytoluene on tert-butylhydroperoxide-induced oxidation of butylated hydroxyanisole, Chem. Pharm. Bull. 31: 1772 (1983).CrossRefGoogle Scholar
  21. 21.
    G.A. Reed, E.A. Brooks and T.E. Eling, Phenylbutazone-dependent epoxidation of 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, J. Biol. Chem. 259: 5591 (1984).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • David C. Thompson
    • 1
  • Young Nam Cha
    • 2
  • Michael A. Trush
    • 1
  1. 1.Dept. Environmental Health SciencesJohns Hopkins University BaltimoreUSA
  2. 2.Dept. PharmacologyYonsei University College of MedicineSeoulKorea

Personalised recommendations