Aromatic hydroxylation and catechol formation: A novel metabolic pathway of the growth promotor zeranol

作者：Hildebrand Andreas; Pfeiffer Erika; Metzler Manfred^*

来源：Toxicology Letters, 2010, 192(3): 379-386.

DOI：10.1016/j.toxlet.2009.11.014

• Zeranol
• alpha-Zearalanol
• Zearalanone
• Aromatic hydroxylation
• Catechols
• Growth promotor

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 a-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 r

• 出版日期2010-2-15