Abstract
The formation of reactive electrophilic intermediates during xenobiotic metabolism which interact with cellular macromolecules is the foundation of current hypotheses on the mechanism of toxicity and carcinogenicity of many chemicals. Aromatic compounds which contain one or more oxygen atoms in functional groups attached to the ring have been extensively studied. These compounds include phenols, hydroquinones and catechols which are oxidized to quinones. Quinones are cytotoxic by virtue of their ability to redox cycle and generate reactive oxygen species and also by their ability to alkylate cellular macromolecules. More recently, compounds such as acetaminophen and phenetidine have been shown to form quinoneimines which are also highly cytotoxic (Dahlin, D.C. et al., 1984; Ross, D. et al., 1985). It is now becoming apparent that other derivatives of the quinonoid moiety may also be highly reactive; for example, quinone methides and imine methides (Mizutani, T. et al., 1982; Yost, G.S., 1989). For comparison, the chemical structures of a quinone, quinoneimine and quinone methide are shown in Figure 1.
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References
Becker, H.-D. (1965). Quinone dehydrogenation. I. The oxidation of monohydric phenols. J. Org. Chem. 30, 982–989.
Brown, Jr., K.S. and Baker, P.N. (1971). Stable ortho-and para-naphthaquinone methides. Tetrahedron Lett. No. 38, 3505–3508.
Clark, G.C. (1988). Acute inhalation toxicity of eugenol in rats. Arch. Toxicol. 62, 381–386.
Dahlin, D.C., Miwa, G.T., Lu, A.Y.H. and Nelson, S.D. (1984). N-acetyl-pbenzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl. Acad. Sci. USA 81, 1327–1331.
Dyall, L.K. and Winstein, S. (1971). Nuclear magnetic resonance spectra and characterization of some quinone methides. J. Am. Chem. Soc. 94, 2196–2199.
Filar, L.J. and Winstein, S. (1961). Preparation and behavior of simple quinone methides. Tetrahedron Lett. No. 25 9–16.
Fotos, P.G., Woolverton, C.J., Van Dyke, K. and Powell, R.L. (1987). Effects of eugenol on polymorphonuclear cell migration and chemi-luminescence. J. Dent. Res. 66, 774–777.
IARC (1985). Eugenol. IARC Monogr. Eval. Carcinog. Risk Chem. Hum. 36, 75–97.
Jurd, L. (1977). Quinones and quinone-methides. I. Cyclization and dimerisation of crystalline ortho-quinone methides from phenol oxidation reactions. Tetrahedron 33, 163–168.
Jurd, L. Fye, R.L. and Morgan, Jr., J. (1979). New types of insect chemo-sterilants. Benzylphenols and benzy1–1,3-benzodioxole derivatives as additives to housefly diet. J. Agr. Food Chem. 27, 1007–1016.
Kozam, G. (1977). The effect of eugenol on nerve transmission. Oral Surg. 44, 799–805.
LaVoie, E.J., Adams, J.D., Reinhardt, J., Rivenson, A. and Hoffman, D. (1986). Toxicity studies on clove cigarette smoke and constituents of clove: determination of the LD50 of eugenol by intratracheal installation. Arch. Toxicol. 59, 78–81.
Leary, G. (1972). Chemistry of reactive lignin intermediates. I. Transients in coniferyl alcohol photolysis. J. Chem. Soc. Perkin Trans. 2 5, 640–642.
Marino, A.A. and Mitchell, J.T. (1972). Lung damage in mice following intraperitoneal injection of butylated hydroxytoluene. Proc. Soc. Exp. Biol. Med. 140, 122–125.
Miller, E.C., Swanson, A.B., Phillips, D.H., Fletcher, T.L., Liem, A. and Miller, J.A. (1983). Structure-activity studies of the carcinogenicities in the mouse and rat of some naturally occurring and synthetic alkenyl-benzene derivatives related to safrole and estragole. Cancer Res. 43, 1124–1134.
Mizutani, T., Ishida, I., Yamamoto, K. and Tajima, K. (1982). Pulmonary toxicity of butylated hydroxytoluene and related alkylphenols: Structural requirements for toxic potency in mice. Toxicol. Appl. Pharmacol. 62, 273–281.
Mizutani, T. Nomura, H., Nakanishi, K. and Fujita, S. (1987). Hepatotoxicity of butylated hydroxytoluene and its analogs in mice depleted of hepatic glutathione. Toxicol. Appl. Toxicol. 87, 166–176.
Moore, H.W., Czerniak, R. and Hamdan, A. (1986). Natural quinones as quinonemethide precursors–ideas in rational drug design. Drugs Exptl. Clin. Res. 12, 475–494.
Morbidity and Mortality Weekly Report (1985). Illnesses possibly associated with smoking clove cigarettes. Vol. 34, pp. 297–299.
Nakagawa, Y., Tayama, K, Nakao, T. and Hiraga, K. (1984). On the mechanism of butylated hydroxytoluene-induced hepatic toxicity in rats. Biochem. Pharmacol. 33, 2669–2674.
Ross, D., Larsson, R., Norbeck, K., Ryhage, R. and Moldéus, P. (1985). Characterization and mechanism of formation of reactive products formed during peroxidase-catalyzed oxidation of p-phenetidine. Mol. Pharmacol. 27, 277–286.
Siegel, S.M. (1956). The biosynthesis of lignin: Evidence for the participation of celluloses as sites for oxidative polymerization of eugenol. J. Am. Chem. Soc. 78, 1753–1755.
Sinha, B.K. and Gregory, J.L. (1981). Role of one-electron and two-electron reduction products of adriamycin and daunomycin in deoxyribonucleic acid binding. Biochem. Pharmacol. 30, 2626–2629.
Suzuki, Y., Sugiyama, K. and Furuta, H. (1985). Eugenol-mediated super-oxide generation and cytotoxicity in guinea pig neutrophils. Japan. J. Pharmacol. 39, 381–386.
Takahashi, O. and Hiraga, K. (1978). Dose-response study of hemorrhagic death by dietary butylated hydroxytoluene (BHT) in male rats. Toxicol. Appl. Pharmacol. 43, 399–406.
Thompson, D., Norbeck, K., Olsson, L.-I., Constantin-Teodosiu, D., Van der Zee, J. and Moldéus, P. (1989). Peroxidase-catalyzed oxidation of eugenol: Formation of a cytotoxic metabolite(s). J. Biol. Chem. 264, 1016–1021.
Thompson, D., Constantin-Teodosiu, D., Norbeck, K., Svensson, B. and Moldéus, P. (1989). Metabolic activation of eugenol by myeloperoxidase and polymorphonuclear leukocytes. Chem. Res. Toxicol. 2, 186–192.
Thompson, D., Constantin-Teodosiu, D., Egestad, B., Mickos, H. and Moldéus, P. (1990). Formation of glutathione conjugates during oxidation of eugenol by microsomal fractions of rat liver and lung. Biochem. Pharmacol. (in press).
Thompson, D., Constantin-Teodosiu, D. and Moldéus, P. (1990). Metabolism and cytotoxicity of eugenol in isolated rat hepatocytes. Chem-Biol. Interactions (manuscript submitted).
Trowbridge, H., Edwall, L. and Panopoulos, P. (1982). Effect of zinc oxide-eugenol and calcium hydroxide on intradental nerve activity. J.Endodontics 8, 403–406.
Turner,A.B. (1964). Quinone Methides. Q. Rev. Chem. Soc. Lond. 18, 347–360.
Wagner, H.-U. and Gompper, R. (1972). Quinone methides. In: The Chemistry of Quinonoid Compounds, S. Patai (ed.), pp. 1145–1178, Wiley, NY.
Webb, Jr., J.G. and Busse11, N.E. (1981). Comparison of the inflammatory response produced by commercial eugenol and purified eugenol. J. Dent. Res. 60, 1724–1728.
Yost, G.S. (1989). Mechanisms of 3-methylindole pneumotoxicity. Chem. Res. Toxicol. 2, 273–279.
Zanarotti, A. (1985). Synthesis and reactivity of vinyl quinone methides. J. Org. Chem. 50, 941–945.
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© 1991 Plenum Press, New York
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Thompson, D., Moldéus, P. (1991). Formation and Reactivity of a Quinone Methide in Biological Systems. In: Witmer, C.M., Snyder, R.R., Jollow, D.J., Kalf, G.F., Kocsis, J.J., Sipes, I.G. (eds) Biological Reactive Intermediates IV. Advances in Experimental Medicine and Biology, vol 283. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5877-0_74
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