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RESEARCH PRODUCT

Metabolism of Chemical Carcinogens

subject

description

Most chemical carcinogens are chemically unreactive per se and need metabolic activation to the ultimate carcinogenic species. The enzyme pattern responsible for the generation and disposition of reactive metabolites constitutes one important early contribution to the control of chemical carcinogenesis. Especially well studied is the group of enzymes responsible for the control of reactive epoxides. Many natural as well as manmade foreign compounds, including pharmaceuticals, possess olefinic or aromatic double bonds. Such compounds can be transformed to epoxides by microsomal monooxygenases present in many mammalian organs. By virtue of their electrophilic reactivity such epoxides may spontaneously react with nucleophilic centers in the cell and thus covalently bind to DNA, RNA and protein. Such alterations of critical cellular macromolecules may disturb the normal biochemistry of the cell and lead to cytotoxic, mutagenic and/or carcinogenic effects. Enzymes controlling the concentration of such epoxides are an important contributing factor in the control of chemical carcinogenesis. Several microsomal monooxygenases exist differing in activity and substrate specificity. With respect to large substrates, some monooxygenases preferentially attack on one specific site different from that attacked by others. Some of these pathways lead to reactive products, others are detoxification pathways. Enzymes metabolizing such epoxides represent a further determining factor. These enzymes include epoxide hydrolases, glutathione transferases and dihydrodiol dehydrogenases. These enzymes do not play a pure inactivating role but can in some cases also act as co-activating enzymes. Enzymes involved in biosynthesis and further metabolism of epoxides differ in quantity and also in substrate specificity between organs, developmental stages, sexes and animal species. Differences in susceptibilities between species and individuals are often causally linked to these metabolic differences.