title: Biotransformation of zearalenone and zearalenols to their major glucuronide metabolites reduces estrogenic activity.
abstract: Zearalenone (ZEN) is a mycotoxin produced by Fusarium fungi. Once ingested, ZEN may be absorbed and metabolised to α- and β-zearalenol (α-ZOL, β-ZOL), and to a lesser extent α- and β-zearalanol (α-ZAL, β-ZAL). Further biotransformation to glucuronide conjugates also occurs to facilitate the elimination of these toxins from the body. Unlike ZEN and its metabolites, information regarding the estrogenic activity of these glucuronide conjugates in various tissues is lacking. ZEN-14-O-glucuronide, α-ZOL-14-O-glucuronide, α-ZOL-7-O-glucuronide, β-ZOL-14-O-glucuronide and β-ZOL-16-O-glucuronide, previously obtained as the major products from preparative enzymatic synthesis, were investigated for their potential to cause endocrine disruption through interference with estrogen receptor transcriptional activity. All five glucuronide conjugates showed a very weak agonist response in an estrogen responsive reporter gene assay (RGA), with activity ranging from 0.0001% to 0.01% of that of 17β-estradiol, and also less than that of ZEN, α-ZOL and β-ZOL which have previously shown estrogenic potencies of the order 17β-estradiol>α-ZOL>ZEN>β-ZOL. Confirmatory mass spectrometry revealed that any activity observed was likely a result of minor deconjugation of the glucuronide moiety. This study confirms that formation of ZEN and ZOL glucuronides is a detoxification reaction with regard to estrogenicity, serving as a potential host defence mechanism against ZEN-induced estrogenic activity.
authors: Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Northern Ireland, United Kingdom. Electronic address: c.frizzell@qub.ac.uk.
authors: Caroline
authors: C
authors: Frizzell
authors: Section for Chemistry and Toxicology, Norwegian Veterinary Institute, Oslo, Norway. Electronic address: silvio.uhlig@vetinst.no.
authors: Silvio
authors: S
authors: Uhlig
authors: Section for Chemistry and Toxicology, Norwegian Veterinary Institute, Oslo, Norway. Electronic address: chris.miles@vetinst.no.
authors: Christopher O
authors: CO
authors: Miles
authors: Norwegian School of Veterinary Science, Oslo, Norway. Electronic address: steven.verhaegen@nmbu.no.
authors: Steven
authors: S
authors: Verhaegen
authors: Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Northern Ireland, United Kingdom. Electronic address: chris.elliott@qub.ac.uk.
authors: Christopher T
authors: CT
authors: Elliott
authors: Section for Chemistry and Toxicology, Norwegian Veterinary Institute, Oslo, Norway. Electronic address: gunnar.eriksen@vetinst.no.
authors: Gunnar S
authors: GS
authors: Eriksen
authors: Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway. Electronic address: morten.sorlie@umb.no.
authors: Morten
authors: M
authors: Sørlie
authors: Norwegian School of Veterinary Science, Oslo, Norway. Electronic address: erik.ropstad@nmbu.no.
authors: Erik
authors: E
authors: Ropstad
authors: Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Northern Ireland, United Kingdom. Electronic address: l.connolly@qub.ac.uk.
authors: Lisa
authors: L
authors: Connolly
mesh_terms: D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D004968:Estrogens, Non-Steroidal / Q000378:metabolism* / Q000633:toxicity*; D017930:Genes, Reporter / Q000187:drug effects; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D009183:Mycotoxins / Q000378:metabolism* / Q000633:toxicity*; D015025:Zearalenone / Q000378:metabolism* / Q000633:toxicity*; D015029:Zeranol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity
chemical_list: D004968:Estrogens, Non-Steroidal; D020719:Glucuronides; D009183:Mycotoxins; C029659:zearalenol; D015025:Zearalenone; D015029:Zeranol
keywords: Estrogenic; Glucuronide; Mycotoxin; Reporter gene assay; Zearalenone