Methyleugenol (ME) has been classified as a "group 2B carcinogen" by IARC. Its positional isomer methylisoeugenol (MIE) has been considered to be of "generally recognized as safe'' status by FDA. ME was more cytotoxic than MIE in cultured mouse primary hepatocytes. The underlying mechanism of this difference is unclear. Our metabolism study revealed ME and MIE were oxidized to epoxides ME-E/MIE-E as well as to phase I metabolites ME-1'-OH (MEOH)/MIE-3'-OH (MIEOH). MEOH was further dehydrogenated to α,β-unsaturated ketone (Michael acceptor, ME-M) by P450 enzymes and was biotransformed to sulfate (ME-S) by sulfotransferases. However, MIEOH was mainly oxidized to α,β-unsaturated aldehyde (Michael acceptor, MIE-M) by P450s subsequently, while MIE-M was rapidly oxidized to cinnamic acid (MIE-C) catalyzed by aldehyde dehydrogenases. Furthermore, cinnamic acid (MIE-C) was found to be a very weak electrophilic metabolite. In vitro and in vivo studies showed that ME possesses higher metabolic activation efficiencies than MIE across three pathways, while MIE shows a higher efficiency in generating MIE-C compared to ME. Taken together, the observed difference in cytotoxicity between ME and MIE may stem from their difference in metabolic pathways due to the difference in the position of their double bonds.
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