Significance of Various Enzymes in the Control of Mutagenic and Carcinogenic Metabolites Derived from Aromatic Structures

Abstract

One important early contribution to the control of chemical carcinogenesis is provided by the enzyme pattern responsible for the generation and disposition of reactive metabolites. Especially well studied is the important group of enzymes responsible for the control of reactive epoxides. Many natural as well as man-made foreign compounds, including Pharmaceuticals, possess olefinic or aromatic double bonds. Such compounds can be transformed to epoxides by microsomal monooxygenases present in very 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, allergenic, mutagenic, and/or carcinogenic effects. Whether such effects will be manifested depends on one hand on the chemical reactivity as well as other properties (geometry, lipophilicity) of the epoxide in question. On the other hand, enzymes controlling the concentration of such epoxides are another important contributing factor. Several microsomal monooxygenases exist differing in activity and substrate specificity. With respect to large substrates, some monooxygenases preferentially attack at one specific site different from that attacked by others. Some of these pathways lead to reactive products, others are detoxification pathways. Moreover, enzymes metabolizing such epoxides represent a further determining factor. These enzymes include epoxide hydrolases and glutathione transferases. These enzymes do not play a pure inactivating role, but can in some cases also act as coactivating enzymes. Enzymes involved in biosynthesis and further metabolism of epoxides differ in quantity and sometimes also in substrate specificity between organs, developmental stages, sexes, and animal species. They therefore represent one important contributing factor to differences in susceptibilities between species and individuals.