Mechanisms of Cytochrome P450-Mediated Formation of Pneumotoxic Electrophiles
Toxicity to lung tissues from systemically circulated chemicals is largely mediated by the bioactivation of these agents by cytochrome P450 enzymes. The toxicity to lung cells is generally caused by reactive electrophiles that are formed as a result of oxygenation or desaturation of the starting xenobiotic molecule. Examples of the reactive intermediates include epoxides, quinone methides, methylene imines, and acyl halides. Selective lung toxicants include naphthalene, butylated hydroxytoluene, 4-ipomeanol, and 3-methylindole (3MI). Examples of pneumotoxic electrophiles that are formed by P450-mediated oxidation of the parent molecules are shown in Figure 1. Also shown are the P450 enzymes that have been proposed to be responsible for the bioactivation of each compound.
KeywordsReactive Intermediate Cytochrome P450 Enzyme Hydrogen Atom Abstraction Quinone Methide Methyl Oxidation
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- 1.Nelson, D.R., Kamataki, T., Waxman, D.J., Guengerich, F.R, Estabrook, R.W., Feyereisen, R. Gonzalez, F.J., Coon, M.J., Gunsalus, I.C., Gotoh, O., Okuda, K., and Nebert, D.W. (1993) The P450 superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol. 12, 1–51.PubMedCrossRefGoogle Scholar
- 3.Buckpitt, A., Buonarati, M., Avey, L.B., Chang, A.M., Morin, D., and Plopper, CG. (1992) Relationship of cytochrome P450 activity to Clara cell cytotoxicity. II. Comparison of stereoselectivity of naphthalene epoxidation in lung and nasal mucosa of mouse, hamster, rat and rhesus monkey. J. Pharmacol. Exp. Therap. 261, 364–372.Google Scholar
- 4.Buckpitt, A. Chang, A.-M., Weir, A., Van Winkle, L. Duan, X., Philpot, R., and Plopper, C. (1995) Relationship of cytochrome P450 activity to Clara cell cytotoxicity. IV. Metabolism of naphthalene and naphthalene oxide in microdissected airways from mice, rats, and hamsters. Mol Pharmacol. 47, 74–81.PubMedGoogle Scholar
- 6.Bolton, J.L., and Thompson, J.A. (1991) Oxidation of butylated hydroxytoluene to toxic metabolites. Factors influencing hydroxylation and quinone methide formation by hepatic and pulmonary microsomes. Drug Metabol. Dispos. 19, 467–472.Google Scholar
- 9.Schulze, J., Richter, E., and Philpot, R.M. (1990) Tissue, species, and substrate concentration differences in the position-selective hydroxylation of N-nitrosodibutylamine. Relationship to the distribution of cytochrome P-450 isozymes 2 (IIB) and 5 (IVB). Drug Metabol. Dispos. 18, 398–402.Google Scholar
- 14.Anttila, S., Vainio, H., Hietanen, E., Camus, A.-M., Malaveille, C., Brun, G., Husgafvel-Pursiainen, K., Heikkila, L., Karjalainen, A., and Bartsch, H. (1992) Immunohistochemical detection of pulmonary cytochrome P450IA and metabolic activities associated with P450IA1 and P450IA2 isozymes in lung cancer patients. Environ. Health Perspec. 98, 179–182.CrossRefGoogle Scholar
- 24.Carlson, J.R. and Dickinson, E.O. (1978) Tryptophan-induced pulmonary edema and emphysema in ruminants. In Effects of Poisonous Plants on Livestock, R.F. Keeler, K.R. Van Kampen, L.F. James, eds., Academic Press, New York, p. 261–262.Google Scholar
- 25.Wynder, E.L., and Hoffman, D. (1967) Certain constituents of tobacco products. In Tobacco and Tobacco Smoke, Studies in Experimental Carcinogenesis, Academic Press, New York, pp. 377–379.Google Scholar
- 37.Skiles, G.L., and Yost G.S. (1990) Mechanisms of oxidative metabolism of the systemic pneumotoxin 3-methylindole in mice, Toxicologist, 10, 67.Google Scholar
- 38.Skiles, G.L., and Yost G.S. (1992) Stable-isotope mechanistic studies on the oxidation of 3-methylindole, Toxicologist, 12, 289.Google Scholar
- 40.Thornton-Manning, J.R., Gonzalez, F.J., and Yost, G.S. (1992) Metabolism of 3-methylindole by vaccinia-expressed cytochrome P450 enzymes,’ Toxicologist, 12, 288.Google Scholar