Journal Article

Metabolism of Methyleugenol in Liver Microsomes and Primary Hepatocytes: Pattern of Metabolites, Cytotoxicity, and DNA-Adduct Formation

Alexander T. Cartus, Kristin Herrmann, Lucas W. Weishaupt, Karl-Heinz Merz, Wolfram Engst, Hansruedi Glatt and Dieter Schrenk

in Toxicological Sciences

Volume 129, issue 1, pages 21-34
Published in print September 2012 | ISSN: 1096-6080
Published online May 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs181
Metabolism of Methyleugenol in Liver Microsomes and  Primary Hepatocytes: Pattern of Metabolites, Cytotoxicity, and  DNA-Adduct Formation

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Methyleugenol (1) is a constituent of many foods, in particular of herbal spices, and is used as flavoring agent in foodstuffs and as fragrance in cosmetics. 1 has been found to be carcinogenic in rodents, its metabolite, 1´-hydroxymethyleugenol (2) acting as proximate DNA-binding carcinogen. We incubated 1 with liver microsomes of rat, bovine, and human origin. We found 2, 3´-hydroxymethylisoeugenol (3), and 6-hydroxymethyleugenol (4) as major metabolites, and 1´-oxomethyleugenol (5), 3´-oxomethylisoeugenol (6), eugenol (9), chavibetol (11), and (RS)-2´,3´-dihydroxy-2´,3´-dihydromethyleugenol (7) as minor metabolites. Methyleugenol-2´,3´-epoxide (8), probably the precursor of 7, could not be detected. Incubations with synthetic metabolites were applied in order to uncover metabolic pathways. Incubations with primary rat hepatocytes revealed mainly nonconjugated 2 and conjugated 4, and minor amounts of partly conjugated 7 and conjugated 9 + 11. The “reactive metabolites” 3, 5, 6, and 8 were not detectable, possibly due to rapid reaction with cellular macromolecules. The highest cytotoxicity (resazurin reduction assay and lactate dehydrogenase leakage assay) was observed for the main metabolite 2 and its secondary metabolite 5 with EC50 values of 50 and 10 µM, respectively. Deoxyadenosine or deoxyguanosine adducts were formed by incubating 1 or metabolites with rat hepatocytes. The rank order of adduct formation was 2 > 1 > 3 > 6, whereas 4, 5, and 8 were inactive. In conclusion, we present a virtually complete pattern of microsomal (rat, bovine, and human) and hepatocellular (rat) metabolites of 1 suggesting the formation of several reactive metabolites possibly involved in carcinogenicity, organ toxicity, and immune reactions.

Keywords: methyleugenol; liver microsomes; alkenylbenzene metabolism; primary rat hepatocytes; DNA adducts

Journal Article.  10415 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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