Methyleugenol is a genotoxic
carcinogen in mice and rats, the liver being the primary target tissue.
Methyleugenol occurs in fennel and many herbs and spices. Furthermore,
methyleugenol-containing
plant extracts and chemically prepared
methyleugenol are used as
flavoring agents. We analyzed surgical human liver samples from 30 subjects for the presence of
DNA adducts originating from
methyleugenol using
isotope-dilution ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Twenty-nine samples unambiguously contained the N (2)-(trans-methylisoeugenol-3'-yl)-2'-deoxyguanosine adduct. A second adduct, N (6)-(trans-methylisoeugenol-3'-yl)-2'-deoxyadenosine, was also found in most samples, but at much lower levels, in agreement with the results from experimental models. The maximal and median levels of both adducts combined were 37 and 13 per 10(8)
nucleosides (corresponding to 4700 and 1700, respectively, adducts per diploid genome). This is the first demonstration of
DNA adducts formed by a
xenobiotic in human liver using UPLC-MS/MS, the most reliable method available. It has been estimated for diverse rat and mouse hepatocarcinogens that 50-5500 adducts per 10(8)
nucleosides are present after repeated treatment at the TD50 (daily dose that halves the probability to stay
tumor-free in long-term studies). We conclude that the exposure to
methyleugenol leads to substantial levels of hepatic
DNA adducts and, therefore, may pose a significant carcinogenic risk.