Uptake, metabolism and mutagenic activity of aromatic glycidyl compounds

Aromatic diglycidyl compounds are very active mutagens when assayed in in vitro tests. In vivo, however, resorcinol diglycidyl ether provided no evidence for the clastogenic activity, while diglycidylaniline exhibited definite mutagenic activity in the micronucleus test. Since the only difference between these two compounds lies in the binding mode of the glycidyl groups to the aromatic nucleus (i.e. ether oxygen vs. aminic nitrogen), this apparent discrepancy in mutagenic activity led to the question of the mechanisms involved in such an activity difference. Although no clear signs of differential uptake or excretion could be detected in mice, differences could be seen in the spectrum of urinary metabolites; while resorcinol diglycidyl ether seemed to become fully converted to the genetically inactive bis-diol compound, a sizeable proportion of diglycidylaniline was converted only to the diol-epoxide. In vitro investigations and enzyme kinetic measurements with postmitochondrial supernatant of rat or mouse liver homogenate (S-9) finally yielded the biochemical explanation for this behaviour, as they showed a very low affinity of the diol-epoxide metabolite of diglycidylaniline for the epoxide hydrolase, normally involved in the degradation of such compounds. The diol-epoxide obtained from resorcinol diglycidyl ether, on the other hand, has an affinity to the degradation enzyme similar to, or even higher than, the one measured with the parent substance.