Chemistry of Covalent Binding: Studies with Bromobenzene and Thiobenzamide
The concept that chemically reactive metabolites of foreign substances could react covalently with cellular constituents to cause biological injury was introduced by J. A. Miller and E. C. Miller almost 40 years ago. 1–3 Since then considerable effort has been spent investigating the chemistry, biochemistry and biological consequences of reactive metabolic intermediates. Our laboratory has been interested in the metabolic activation, covalent binding and hepatotoxicity of two relatively simple organic compounds, bromobenzene and thiobenzamide. Our long term objective has been to determine the identity of their reactive metabolites, the chemistry of their covalent binding to cellular macromolecules and the relationship of the various types of covalent binding events to the biological changes which follow. This report summarizes some of our recent efforts toward these objectives.
KeywordsCovalent Binding Butylate Hydroxy Toluene Substituent Effect Reactive Metabolite Tritiated Water
Unable to display preview. Download preview PDF.
- 1.E. C. Miller and J. A. Miller, The presence and significance of bound aminoazo dyes in the livers of rats fed p-dimethylaminoazobenzene. Cancer Res. 7: 468–480 (1947).Google Scholar
- 2.E. C. Miller and J. A. Miller, In vivo combinations between carcinogens and tissue constituents and their possible role in carcinogenesis. Cancer Res. 12: 547–556 (1952).Google Scholar
- 8.K. T. Finley, The addition-substitution chemistry of quinones, in: “The chemistry of quinoid compounds, S. Patai, ed., John Wiley and Sons, New York (1974), pp 880–900.Google Scholar
- 9.T. J. Monks, L. R. Pohl, J. R. Gillette, M. Hong, R. J. Highet, J. A. Ferrretti and J. A. Hinson, Stereoselective formation of two bromobenzene-glutathione conjugates. Chem.-Biol. Interactions 41: 203–216 (1982).Google Scholar
- 12.R. P. Hanzlik and J. R. Cashman, Micrrosomal metabolism of thioben-zamide and thiobenzamide S-oxide. Drug Metab. Disposition, 11: 201–205 (1983).Google Scholar
- 17.J. R. Cashman, K. K. Parikh, G. J. Traiger and R. P. Hanzlik, Relative hepatotoxicity of ortho and meta monosubstituted thiobenzamides in the rat. Chem.-Biol. Interactions 45: 341–347 (1983).Google Scholar
- 20.J. R. Cashman, Ph.D. Thesis, University of Kansas, 1982.Google Scholar
- 24.R. P. Hanzlik, Effects of substituents of reactivity and toxicity of chemically reactive intermediates. Drug Metab. Rev. 13: 207–234 (1982).Google Scholar