title: In vitro phase I metabolism of cis-zearalenone.
abstract: 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-configured 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 that of 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. In 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 dominant 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. Because these routes have been reported for trans-ZEN, we conclude that the phase I metabolism of cis-ZEN is essentially similar to that of 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 higher estrogenicity.
authors.affiliation: Department of Analytical Chemistry; Reference Materials, Federal Institute for Materials Research and Testing (BAM) , Richard-Willstaetter-Strasse 11, 12489 Berlin, Germany.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Drzymala
authors.forename: Antje J
authors.initials: AJ
authors.lastname: Herrmann
authors.forename: Ronald
authors.initials: R
authors.lastname: Maul
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Leif-Alexander
authors.initials: LA
authors.lastname: Garbe
authors.forename: Matthias
authors.initials: M
authors.lastname: Koch
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004968:Estrogens, Non-Steroidal / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D050216:Metabolic Detoxication, Phase I; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D015025:Zearalenone / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004968:Estrogens, Non-Steroidal; D015025:Zearalenone