title: Aromatic hydroxylation and catechol formation: a novel metabolic pathway of the growth promotor zeranol.
abstract: Alpha-zearalanol (alpha-ZAL, zeranol) is a macrocyclic resorcylic acid lactone, which is highly estrogenic and used as a growth promotor for cattle in various countries. Little is known about the phase I metabolism of alpha-ZAL. We now report that alpha-ZAL and its major metabolite zearalanone (ZAN) are extensively monohydroxylated at the aromatic ring by microsomes from human liver in vitro. This novel pathway leads to catechols, the chemical structures of which were unambiguously established by the use of deuterium-labeled alpha-ZAL and ZAN, and by the synthesis of authentic standards. The aromatic hydroxylation of alpha-ZAL is almost exclusively mediated by the human cytochrome P450 (hCYP) 1A2 isoform. The catechol metabolites of alpha-ZAL and ZAN are unstable and readily oxidized to quinones, which could be detected among the metabolites of alpha-ZAL and ZAN generated by human hepatic microsomes and hCYP1A2. Furthermore, the quinone metabolites are able to form covalent adducts with N-acetylcysteine (NAC), as several of such adducts were found in microsomal incubations fortified with NAC. Aromatic hydroxylation of alpha-ZAL was also observed with bovine, porcine and rat hepatic microsomes. Further studies are needed to demonstrate the catechol pathway of alpha-ZAL in vivo and to assess its toxicological significance.
authors.affiliation: Institute of Applied Biosciences, Chair of Food Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hildebrand
authors.forename: Erika
authors.initials: E
authors.lastname: Pfeiffer
authors.forename: Manfred
authors.initials: M
authors.lastname: Metzler
mesh_terms: D000818:Animals; D002396:Catechols / Q000378:metabolism; D002417:Cattle; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D013552:Swine; D015025:Zearalenone / Q000378:metabolism; D015029:Zeranol / Q000378:metabolism*
chemical_list: D002396:Catechols; D004968:Estrogens, Non-Steroidal; D020033:Protein Isoforms; D015025:Zearalenone; D015029:Zeranol; D019388:Cytochrome P-450 CYP1A2