Influence of foreign compounds on formation and disposition of reactive metabolites

Abstract

Many toxic compounds are unreactive and need biotransformation in order to exert their toxic effects. Several enzymes control the formation or disposition of reactive metabolites. Especially well studied is the group of enzymes responsible for the control of reactive epoxides. Such epoxides may bind spontaneously to DNA, RNA and protein. These alterations of critical cellular macromolecules may disturb the normal biochemistry of the cell and lead to cytotoxic, allergenic, mutagenic and carcinogenic effects. Whether these effects will be manifested depends on the chemical reactivity as well as on other properties (geometry, lipophilicity) of the epoxide in question. Enzymes controlling the concentration of epoxides are another important contributing factor. Several microsomal monooxygenases exist. Some monooxygenases preferentially attack large substrates at single sites, specific for each enzyme. Some of these steps produce reactive metabolites; others are detoxification pathways. Enzymes that metabolize the epoxides represent a further determining factor. These enzymes include epoxide hydrolase (EC 3.3.2.3) and glutathione transferases (EC 2.5.1.18), which do not play a purely inactivating role but can, in some cases, act also as coactivating enzymes. Some of these enzymes have been shown to be influenced by foreign compounds. Acute effects by activation and inhibition of the enzymes as well as long-term effects by induction and repression have been observed. Since different foreign compounds differentially influence various enzymes, they can produce changes not only in overall metabolic activity but also changes in metabolite pattern and in selective toxicities.