Metabolism of genotoxic agents: control of reactive epoxides by hydrolase and transferase reactions.

Hydrolase and transferase reactions play dual roles in the control of carcinogenic and mutagenic species. In some instances, they play an activating or coactivating role. However, as far is known, in most cases they are wholly or predominantly inactivating mechanisms. The important hydrolase and transferase enzymes that are involved in the control of reactive epoxides are particularly well studied. These include epoxide hydrolases and glutathione transferases that react directly with electrophilic epoxides, as well as conjugating enzymes, such as glucuronosyl transferases and sulfotransferases, that sequester nucleophilic precursors of complex epoxides such as phenols and dihydrodiols. These, and other enzymes that are involved in biosynthesis and the further metabolism of reactive metabolites, are an important contributing factor to differences in susceptibility, since they differ in quantity and, sometimes, also in substrate specificity between organs, developmental stages, sexes and animal species. Knowledge of these variables is, therefore, required for a rational extrapolation to humans of the toxicity data obtained in available test systems; the rational interpretation of data obtained by biomonitoring requires similar knowledge.