Bioactivation of zearalenone by porcine hepatic biotransformation

Abstract

-Zearalenone (ZEA) is a resorcylic acid lactone derivative produced by various Fusarium species that are widely found in food and feeds. The structure of zearalenone is flexible enough to allow a conformation able to bind to mammalian oestrogen receptors, where it acts as an agonist. Using oestrogen-dependent Human Breast Cancer (MCF-7) cells, the oestrogenic activity of zearalenone and its derivatives were compared using 17 β-oestradiol as a positive control. The results obtained demonstrate that the oestrogenic potency of ZEA derivatives could be ranked in the following order: α-zearalenol > α-zearalanol > zearalenone > β-zearalenol. Since pigs have been reported to be among the most sensitive animal species, biotransformation studies with pig liver subcellular fractions were conducted. These studies indicated that α-zearalenol is the main hepatic metabolite of zearalenone in pigs, and it is assumed that 3α-and 3β-hydroxysteroid dehydrogeneases are involved in the hepatic biotransformation, since the formation of α-zearalenol and β-zearalenol could be inhibited by prototypic substrates for either enzyme. The bioactivation of ZEA into the more active α-zearalenol seems to provide a possible explanation for the observed high sensitivity of pigs towards feedingstuffs contaminated with the mycotoxin. zearalenone / MCF-7 cells / oestrogenic effects / biotransformation / pigs

Novel oxidative metabolites of the mycoestrogen zearalenone in vitro

“…It is now important to clarify whether oxidative ZEN metabolites are also formed in vivo, and to elucidate their chemical structures and biological activities. The reductive metabolites a-zearalenol and -zearalanol have long been known to be stronger estrogens than ZEN, and their pronounced formation in pigs may explain the high susceptibility of this animal species to the hormonal effects of ZEN-contaminated feed [22,23]. Likewise, it is conceivable that compounds with increased estrogenicity are among the monohydroxylated ZEN metabolites reported here.…”

Alimentação de leitoas pré-púberes com dietas contendo zearalenona

“…Também há variação entre os produtos da biotransformação hepática da ZEA quanto ao efeito estrogênico, sendo o α-zearalenol qualificado como de atividade mais intensa que a ZEA e o β-zearalenol (Cellius et al, 1999). Logo, a biotransformação hepática da ZEA em α-zearalenol pode ser considerada uma etapa de ativação da toxina (Malekinejad et al, 2005). A produção predominante de α-zearalenol em suínos, associada à maior afinidade desse metabólito pelos receptores estrogênicos, justifica a alta sensibilidade da espécie à micotoxina (Malekinejad et al, 2006).…”

“…Após a ingestão, a ZEA é rapidamente absorvida pelas células do trato gastrintestinal (Ramos et al, 1996), sendo a absorção estimada em 85% nos monogástricos (Malekinejad et al, 2005). A flexibilidade na conformação espacial da ZEA e dos produtos de sua biotransformação hepática permite a competição com o 17β-estradiol por receptores estrogênicos das células uterinas, hipotalâmicas, hipofisárias e das glândulas mamárias (Kuiper-Goodman et al, 1987).…”

The role of mycotoxins in pig reproduction: a review

“…Alpha-hydroxylation results in an increase of estrogenic potency and explains the species specific sensitivity towards ZEA intoxications, whereas glucuronidation capacity inactivates ZEA. In comparison with other species, pigs have a low glucuronidation capacity making them more sensitive to ZEA (Malekinejad et al, 2005;FinkGremmels and Malekinejad, 2007).…”