In Vitro phase I metabolism of cis-zearalenone.
The present study investigates the in vitro phase I metabolism of cis-zearalenone (cis-ZEN) in rat liver microsomes and human liver microsomes. cis-ZEN is an often ignored isomer of the trans-configurated Fusarium mycotoxin zearalenone (trans-ZEN). Upon the influence of (UV-) light, trans-ZEN isomerizes to cis-ZEN. Therefore, cis-ZEN is also present in food and feed. The aim of our study was to evaluate the in vitro phase I metabolism of cis-ZEN in comparison to trans-ZEN. As a result, an extensive metabolization of cis-ZEN is observed for rat and human liver microsomes as analyzed by HPLC-MS/MS and high-resolution MS. Kinetic investigations based on the substrate depletion approach showed no significant difference in rate constants and half-lives for cis– and trans-ZEN in rat microsomes. By contrast, cis-ZEN was depleted about 1.4 fold faster than trans-ZEN in human microsomes. The metabolite pattern of cis-ZEN revealed a total of 10 phase I metabolites. Its reduction products α- and β-cis-zearalenol (α- and β-cis-ZEL) were found as metabolites in both species with α-cis-ZEL being a major metabolite in rat liver microsomes. Both compounds were identified by co-chromatography with synthesized authentic standards. A further major metabolite in rat microsomes was monohydroxylated cis-ZEN. In human microsomes, monohydroxylated cis-ZEN is the single dominating peak of the metabolite profile. Our study discloses three metabolic pathways for cis-ZEN: reduction of the keto-group, monohydroxylation and a combination of both. Since these routes have been reported for trans-ZEN, we conclude that the phase I metabolism of cis-ZEN is essentially similar to its trans-isomer. As trans-ZEN is prone to metabolic activation leading to the formation of more estrogenic metabolites, the novel metabolites of cis-ZEN reported in this study, in particular α-cis-ZEL, might also show a higher estrogenicity.
Drzymala, S.S.; Herrmann, A.J.; Maul, R.; Pfeifer, D.; Garbe, L.A.; Koch, M. 2014. In Vitro phase I metabolism of cis-zearalenone. Chemical Research in Toxicology, DOI: 10.1021/tx500312g.