Reactions of Reactive Metabolites with Hemoproteins—Toxicological Implications

Covalent Alteration of Hemoproteins
  • Yoichi Osawa
  • Kashime Nakatsuka
  • Mark S. Williams
  • James T. Kindt
  • Mikiya Nakatsuka
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 387)


It was suggested in 1971 based on studies with the hepatotoxic agent, bromobenzene, that metabolism of chemicals to reactive intermediates could play a central role in toxicological processes involved with xenobiotics (Brodie et al., 1971). Over the subsequent 20 years, studies on a variety of chemicals have supported such a notion due to the correlation of the level of protein bound metabolites with toxicity (Hinson & Roberts, 1992). Only in a few cases, however, have the proteins involved or the nature of the covalent modifications been determined and in no case has a direct toxicological role for the altered proteins been shown. One of the best characterized cellular targets of reactive intermediates are the liver microsomal P450 cytochromes (Ortiz de Montellano & Correia, 1983; Halpert & Stevens, 1991), which in many instances are the enzymes responsible for the generation of the reactive metabolites. It is known that at least three pathways exist for the covalent alteration of the cytochrome P450, one that involves alteration of the heme, a second that involves alteration of the protein, and a third that involves the crosslinking of heme to the protein (Scheme I) (Osawa & Pohl, 1989). Although the alterations of the heme or the protein have been well documented (Ortiz de Montellano, 1990; Halpert, 1982; Halpert, Miller, & Gorsky, 1985; Roberts et al., 1994; Roberts, Hopkins, Alworth, & Hollenberg, 1993; Bryant, Skipper, Tannenbaum, & Maclure, 1987; Gorelick, Hutchins, Tannenbaum, & Wogan, 1989), the protein bound heme adducts have not been structurally defined, due to the complexity of the cytochrome P450 system and the potential reactions that can occur after initial heme alteration.


Reactive Metabolite Methyl Violet Human Hemoglobin Myocardial Ischemia Reperfusion Injury Trichloromethyl Radical 
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Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Yoichi Osawa
    • 1
  • Kashime Nakatsuka
    • 1
  • Mark S. Williams
    • 2
  • James T. Kindt
    • 1
  • Mikiya Nakatsuka
    • 1
  1. 1.Molecular and Cellular Toxicology SectionLaboratory of Molecular Immunology, NHLBIBethesdaUSA
  2. 2.Experimental Immunology BranchNCI National Institutes of HealthBethesdaUSA

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