Comparative induction of unscheduled DNA synthesis in cultured rat hepatocytes by allylbenzenes and their 1′-hydroxy metabolites

The allylbenzenes estragole, methyleugenol and safrole are hepatocarcinogens in rodents at very high doses, but allylbenzene itself is neither hepatotoxic nor hepatocarcinogenic. To elucidate further the significance of metabolic 1'-hydroxylation in the carcinogenicity of the allylbenzenes and to give further insights into the structure-metabolism-genotoxicity relationships of these compounds, comparative data were established on the ability of estragole, methyleugenol, safrole, allylbenzene and their 1'-hydroxy metabolites to induce unscheduled DNA synthesis (UDS) in hepatocytes derived from male Fischer 344 rats. Cytotoxicity was assessed by lactate dehydrogenase leakage. The first three compounds increased UDS in a dose-related fashion but allylbenzene was non-genotoxic. 1'-Hydroxyestragole, -methyleugenol and -safrole were more potent genotoxins than their parent compounds. This difference in genotoxicity indicates the importance of the attachment of the electron-withdrawing methoxy or methylenedioxy substituents to the benzene ring. The non-linear dose-response curves for genotoxicity obtained with the allylbenzenes and their 1'-hydroxy metabolites indicate that it is important to consider dose-dependence in metabolism when interpreting the significance to humans of animal data obtained with very high doses of the compounds studied. It is likely that the use of these high doses markedly overestimates the potential hazard to humans of low doses of allylbenzenes, which generate only very small quantities of genotoxic metabolites.