Significance of various enzymes in the control of reactive metabolites

Abstract

Most chemical carcinogens are relatively inert and need metabolic activation to the ultimately carcinogenic species. The concentration of such species is controlled by several different enzymes. 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 many mammalian organs. By virtue of their electrophilic reactivity, such epoxides may spontaneously react with nucleophilic centres 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, allergic and/or carcinogenic effects. Whether such effects will be manifested depends on one hand, on the chemical reactivity as well as other properties such as geometry and lipophilicity of the epoxide in question. On the other hand, enzymes controlling the concentration of such epoxides represent a further important contributing factor: for example, several microsomal monooxygenases exist, differing in substrate specificity. With respect to large substrates, certain monooxygenases preferentially attack at a specific site different from that attacked by others. Some of these pathways lead to reactive products, whilst others are detoxification pathways. Moreover, enzymes metabolizing such epoxides represent a further determining factor. These enzymes include epoxide hydrolases and glutathione transferases. These enzymes are not solely inactivating but can also in some cases act as activating enzymes. Finally, precursor-sequestering enzymes contribute indirectly but substantially to the control of reactive metabolites. All these enzymes differ in quantity, subcellular localization and sometimes also in substrate specificity between organs, development stages, sexes and species. They therefore represent an important contributing factor to differences in susceptibilities. Further factors responsible for differences in susceptibilities include DNA repair capabilities, rate of replicative DNA synthesis and various host defense mechanisms.