Covalent Binding of Carcinogens to Tissue Macromolecules

The detection of the covalent binding of aminoazo dyes to liver protein in rats fed DAB and similar dyes (Miller and Miller, 1947) depended on the intense red color of these dyes in acid as a marker for the whole p-aminoazobenzene structure (Cilento et al., 1956). The protein-bound dye from DAB was the first identification of an adduct of a metabolite of a carcinogen to a macromolecule in a tissue undergoing carcinogenesis. The amount of these adducts correlated strongly with the carcinogenicities of DAB and its ring-methyl derivatives in the rat liver (Miller et al., 1949). Surprisingly, no protein-bound dye could be detected in the liver tumors caused by DAB, even during its administration. This led to a deletion theory of the mechanism of tumor formation by this carcinogen (E. C. Miller and Miller, 1947; J. A. Miller and Miller, 1953). Thus, if dye bound to proteins that controlled growth led to a loss of these proteins in certain cells, then these cells would become tumor cells. This research was done in the 1940s when the structures and functions of DNA and RNA were poorly understood. Attempts were made to find nucleic acid-bound dye but none was found (Miller and Miller, 1952). Only much later was it found that the structure of the principal nucleic acid-bound dye from DAB did not show a red color in acid (Lin etal., 1975b). In the 1950s, 14C-labeled carcinogens became available and it was shown that various chemical carcinogens became covalently bound to proteins, RNAs, and DNA in vivo (Miller and Miller, 1985). The seminal paper by Watson and Crick (1953) on the structure and genetic function of DNA soon directed studies on covalent binding of carcinogens to DNA, and the protein-binding of these agents was less studied. Attention also turned to the metabolism and possible reactive forms of chemical carcinogens.

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