Significance of Covalent Binding of Chemically Reactive Metabolites of Foreign Compounds to Proteins and Lipids
Shortly after the initial finding by the Millers (Miller and Miller, 1947; Miller et al., 1949) that the administration of N,N-dimethyl-4-aminoazobenzene (DAB) to rats resulted in the covalent binding of metabolites of the azo-dye to liver proteins, there was considerable interest in the possibility that the covalent binding to specific proteins might initiate the series of events that led to carcinogenesis. Recognition that tumors probably develop from the transformation of cells in which alterations were inherited by daughter cells, however, led to the mutagenesis hypothesis of carcinogenesis, and the emphasis of research shifted from covalent binding of metabolites to proteins to their covalent binding to DNA and RNA. Since that time, however, many foreign compounds have been shown to be transformed to chemically reactive metabolites that combine with proteins and lipids. Indeed, even carcinogens that presumably evoke mutagenic changes in DNA almost invariably also become covalently bound to proteins.
KeywordsParent Compound Covalent Binding Blood Flow Rate Reactive Metabolite Second Order Reaction
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