Aromatic hydroxylation is a major metabolic pathway of the mycotoxin zearalenone in vitro.
Zearalenone (ZEN) is a common mycotoxin, for which only reductive metabolites have been identified so far. We now report that ZEN is extensively monohydroxylated by microsomes from human liver in vitro. Two of the major oxidative metabolites arise through aromatic hydroxylation and are catechols. Their chemical structures have been unambiguously determined by using deuterium-labeled ZEN and by comparison with authentic reference compounds. Moreover, both catechol metabolites of ZEN were substrates of the enzyme catechol-O-methyl transferase. One of the monomethyl ethers represented the major metabolite when ZEN was incubated with rat liver slices, thus demonstrating that catechol formation also takes place under in vivo-like conditions. Out of ten major human cytochrome P450 (hCYP) isoforms only hCYP1A2 was able to hydroxylate ZEN to its catechols with high activity. Catechol formation represents a novel pathway in the metabolism of ZEN and may be of toxicological relevance.
Pfeiffer
Erika
E
Institute of Applied Biosciences, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
Hildebrand
Andreas
A
Damm
Georg
G
Rapp
Andreas
A
Cramer
Benedikt
B
Humpf
Hans-Ulrich
HU
Metzler
Manfred
M
D000818:Animals; D002394:Catechol O-Methyltransferase / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D008745:Methylation; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D015025:Zearalenone / Q000378:metabolism*
D015025:Zearalenone; D003577:Cytochrome P-450 Enzyme System; D002394:Catechol O-Methyltransferase