In vitro cytochrome p450 formation of a mono-hydroxylated metabolite of zearalenone exhibiting estrogenic activities: possible occurrence of this metabolite in vivo.
The mycoestrogen zearalenone (ZEN), as well as its reduced metabolites, which belong to the endocrine disruptor bio-molecule family, are substrates for various enzymes involved in steroid metabolism. In addition to its reduction by the steroid dehydrogenase pathway, ZEN also interacts with hepatic detoxification enzymes, which convert it into hydroxylated metabolites (OH-ZEN). Due to their structures to that of estradiol, ZEN and its derived metabolites bind to the estrogen receptors and are involved in endocrinal perturbations and are possibly associated with estrogen-dependent cancers. The primary aim of this present study was to identify the enzymatic cytochrome P450 isoforms responsible for the formation of the most abundant OH-ZEN. We thus studied its in vitro formation using hepatic microsomes in a range of animal model systems including man. OH-ZEN was also recovered in liver and urine of rats treated orally with ZEN. Finally we compared the activity of ZEN and its active metabolites (alpha-ZAL and OH-ZEN) on estrogen receptors using HeLa ER-alpha and ER-beta reporter cell lines as reporters. OH-ZEN estrogenic activities were revealed to be limited and not as significant as those of ZEN or alpha-ZAL.
Bravin
Frederique
F
CEA Saclay, iBiTec-S, SB2SM and URA CNRS, Gif sur Yvette Cedex F-91191, France. Frederique.bravin@gmail.com
Duca
Radu C
RC
Balaguer
Patrick
P
Delaforge
Marcel
M
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006900:Hydroxylation; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D023421:Models, Animal; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015025:Zearalenone / Q000032:analysis / Q000378:metabolism* / Q000652:urine
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D020033:Protein Isoforms; D015025:Zearalenone; D003577:Cytochrome P-450 Enzyme System