Metabolic Activation of Chemical Carcinogens

As studies on the reactions of carcinogens with cellular macromolecules progressed, it became apparent that most of these interactions resulted from covalent bond formation between an elec-trophilic form of the carcinogen and the nucle-ophilic sites in proteins (e.g., sulfur, oxygen, and nitrogen atoms in cysteine, tyrosine, and histi-dine, respectively) and nucleic acids (e.g., purine or pyrimidine ring nitrogens and oxygens). Frequently, the parent compound itself did not interact in vitro with macromolecules until it had been incubated with liver homogenates or liver microsomal fractions. These studies led to the realization that metabolic activation of cer tain carcinogenic agents is necessary to produce the "ultimate carcinogen" that actually reacts with crucial molecules in target cells. With the exception of the very chemically reactive alky-lating agents, which are activated in aqueous solution at physiologic pH (e.g., N-methyl-N-nitrosourea), and the agents that intercalate into the DNA double helix by forming tight non-covalent bonds (e.g., daunorubicin), most of the known chemical carcinogens undergo some metabolic conversions that appear to be required for their carcinogenic action. Some examples of these metabolic conversions are given next.

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