Safrole: Its metabolism, carcinogenicity and interactions with cytochrome P-450

Abstract

A review of studies on safrole metabolism shows that the compound gives rise to a large number of metabolites by two major pathways, oxidation of the allyl side chain and oxidation of the methylenedioxy group with subsequent cleavage to form a catechol. The mechanism by which safrole exerts the weak hepatocarcinogenicity that has been demonstrated in rats and mice is considered on the basis of published work and recent studies by the authors. Metabolic conversion of the allyl group gives rise to intermediates capable of covalent binding with DNA and protein, and recent findings are compatible with conversion of the methylenedioxy group to a carbene, which forms ligand complexes with the haem moiety of cytochromes P-450 and P-448. It is suggested that while the allyl group is responsible for the mutagenic potential of safrole, the methylenedioxy moiety may be associated with epigenetic aspects of carcinogenicity. © 1981.