Investigation of the role of the 2',3'-epoxidation pathway in the bioactivation and genotoxicity of dietary allylbenzene analogs.
The genotoxic potential of naturally occurring allylbenzene analogs, including safrole, eugenol, estragole, and others, has been examined in many studies over the past 30 years. It has been established that these compounds are subject to biotransformation in the liver, which can lead to the formation of reactive electrophilic intermediates. The major route of bioactivation is via hydroxylation of the 1' carbon atom of the allylic side chain. We have synthesized 2',3'- (allylic) epoxide derivatives of allylbenzene, estragole eugenol and safrole, and have used them to characterize the genotoxic potential of epoxidation at the allylic double bond for allylbenzene and its naturally occurring analogs. In order to assert that this pathway has the potential for genotoxicity, it is necessary to demonstrate (1) that epoxide metabolites of these compounds are capable of forming covalent adducts with DNA bases; and (2) that these epoxide metabolites are actually formed in vivo. We have demonstrated that allylic epoxides derived from allylbenzene and estragole are capable of forming covalent adducts with all four deoxyribonucleotides in vitro and, in the case of deoxyguanosine, form at least four different adducts. We also deduce, from evidence obtained using the isolated perfused rat liver, that formation of potentially genotoxic 2',3' epoxide metabolites occurs readily in vivo, but that these metabolites are rapidly further metabolized to less toxic dihydrodiol or glutathione conjugates. We conclude that 2',3' epoxide metabolites of allylbenzene analogs are formed in vivo and that these epoxides are sufficiently reactive to facilely form covalent bonds with DNA bases. Epoxide formation at the allylic double bond represents, therefore, a potentially genotoxic bioactivation pathway for allylbenzene analogs. However, comparison of the relative kinetics of epoxide metabolism and epoxide formation suggests that a wide margin of protection from DNA covalent adduct formation exists in the rat liver, thus preventing genotoxicity resulting from this pathway to any significant degree. In this regard, we have also observed that the general rate of epoxide hydrolysis is much greater in human liver than in rat liver. We therefore suggest that while the epoxidation pathway poses a potential genotoxic threat to humans, no actual genotoxicity occurs as a result of this metabolic pathway.
Guenthner
T M
TM
Department of Pharmacology, College of Medicine, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612, USA. tmg@uic.edu
Luo
G
G
D000818:Animals; D001555:Benzene Derivatives / Q000493:pharmacokinetics* / Q000633:toxicity; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis / Q000187:drug effects; D004032:Diet; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000493:pharmacokinetics* / Q000633:toxicity; D006168:Guinea Pigs; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics* / Q000633:toxicity; D010477:Perfusion; D011817:Rabbits; D051381:Rats; D013045:Species Specificity
D001555:Benzene Derivatives; D018736:DNA Adducts; D004852:Epoxy Compounds; D009153:Mutagens; C091757:allylbenzene 2',3'-epoxide; D004247:DNA; D004851:Epoxide Hydrolases