Abundance of DNA adducts of methyleugenol, a rodent hepatocarcinogen, in human liver samples

作者：Herrmann Kristin; Schumacher Fabian; Engst Wolfram; Appel Klaus E; Klein Kathrin; Zanger Ulrich M; Glatt Hansruedi^*

来源：Carcinogenesis, 2013, 34(5): 1025-1030.

DOI：10.1093/carcin/bgt013

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 chromatographytandem 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 505500 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.

• 出版日期2013-5