Catechol metabolites of the mycotoxin zearalenone are poor substrates but potent inhibitors of catechol- O -methyltransf
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ORIGINAL PAPER
Catechol metabolites of the mycotoxin zearalenone are poor substrates but potent inhibitors of catechol-O-methyltransferase Erika Pfeiffer & Daniel Wefers & Andreas A. Hildebrand & Stefanie C. Fleck & Manfred Metzler
Received: 28 January 2013 / Revised: 11 March 2013 / Accepted: 12 March 2013 / Published online: 5 April 2013 # Society for Mycotoxin Research and Springer-Verlag Berlin Heidelberg 2013
Abstract The mycotoxin zearalenone (ZEN) elicits estrogenic effects and is biotransformed to two catechol metabolites, in analogy to the endogenous steroidal estrogen 17ßestradiol (E2). Previous studies have shown that the catechol metabolites of ZEN have about the same potency to induce oxidative DNA damage as the catechol metabolites of E2, but are less efficiently converted to their methyl ethers by human hepatic catechol-O-methyltransferase (COMT). Here, we report that the two catechol metabolites of ZEN, i.e. 13-hydroxy-ZEN and 15-hydroxy-ZEN, are not only poor substrates of human COMT but are also able to strongly inhibit the O-methylation of 2-hydroxy-E2, the major catechol metabolite of E2. 15-Hydroxy-ZEN acts as a noncompetitive inhibitor and is about ten times more potent than 13-hydroxy-ZEN, which is an uncompetitive inhibitor of COMT. The catechol metabolites of ZEN were also shown to inhibit the O-methylation of 2-hydroxy-E2 by hepatic COMT from mouse, rat, steer and piglet, although to a lesser extent than observed with human COMT. The powerful inhibitory effect of catechol metabolites of ZEN on COMT may have implications for the tumorigenic activity of E2, because catechol metabolites of E2 elicit genotoxic effects, and their impaired O-methylation may increase the tumorigenicity of steroidal estrogens. Keywords Zearalenone . Catechol metabolites . CatecholO-methyltransferase . Inhibition . 2-hydroxyestradiol E. Pfeiffer : D. Wefers : A. A. Hildebrand : S. C. Fleck : M. Metzler (*) Institute of Applied Biosciences, Unit of Food Toxicology, Karlsruhe Institute of Technology (KIT), Adenauerring 20a, D-76131, Karlsruhe, Germany e-mail: [email protected]
Abbreviations COMT Catechol-O-methyltransferase DAD Diode array detection DMSO Dimethylsulfoxide E1 Estrone E2 17ß-estradiol EGCG (-)Epigallocatechin-3-O-gallate HO Hydroxy HPLC High performance liquid chromatography IC50 Concentration at 50 % inhibition MP Methylation product SAM S-adenosyl-L-methionine ZEL Zearalenol ZEN Zearalenone
Introduction The mycotoxin zearalenone (ZEN; Fig. 1) is frequently found as a contaminant in corn and other crops infested by Fusarium species (EFSA 2011; Zinedine et al. 2007; Gromadska et al. 2008; Maragos 2010). Due to the high estrogenicity of ZEN and several of its metabolites, consumption of high levels of ZEN can cause endocrine disruptive effects in domestic animals and possibly in humans (EFSA 2011; Metzler et al. 2010; Massart and Saggese 2010). Moreover, an increased incidence of pituitary tumors and liver adenoma was observed in mice after being fed a diet containing ZEN for 2 years (NTP 1982)
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