Abstract
Zearalenone-14-glucoside (ZEN-14G), the modified mycotoxin of zearalenone (ZEN), has attracted considerable attention due to its high potential to be hydrolyzed into ZEN, which would exert toxicity. It has been confirmed that the microflora could metabolize ZEN-14G to ZEN. However, the metabolic profile of ZEN-14G and whether it could be deglucosidated in the liver are unknown. To thoroughly investigate the metabolism of ZEN-14G, in vitro metabolism including phase I and phase II metabolism was studied using liquid chromatography coupled to high-resolution mass spectrometry. Additionally, in vivo metabolism of ZEN-14G was conducted in model animals, rats, by oral administration. As a result, 29 phase I metabolites and 6 phase II metabolites were identified and significant inter-species metabolic differences were observed as well. What is more, ZEN-14G could be considerably deglucosidated into its free form of ZEN after the incubation with animals and human liver microsomes in the absence of NADPH, which was mainly metabolized by human carboxylesterase CES-I and II. Furthermore, results showed that the major metabolic pathways of ZEN-14G were deglucosylation, hydroxylation, hydrogenation and glucuronidation. Although interspecies differences in the biotransformation of ZEN-14G were observed, ZEN, α-ZEL-14G, β-ZEL-14G, α-ZEL, ZEN-14G-16GlcA and ZEN-14GlcA were the major metabolites of ZEN-14G. Additionally, a larger yield of 6-OH-ZEN-14G and 8-OH-ZEN-14G was also observed in human liver microsomes. The obtained data would be of great importance for the safety assessment of modified mycotoxin, ZEN-14G, and provide another perspective for risk assessment of mycotoxin.
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References
Berthiller F, Crews C, Dall’Asta C et al (2013) Masked mycotoxins: a review. Mol Nutr Food Res 57(1):165–186
Binder SB, Schwartz-Zimmermann HE, Varga E et al (2017) Metabolism of zearalenone and its major modified forms in pigs. Toxins (Basel). https://doi.org/10.3390/toxins9020056
Broekaert N, Devreese M, De Baere S, De Backer P, Croubels S (2015) Modified Fusarium mycotoxins unmasked: from occurrence in cereals to animal and human excretion. Food Chem Toxicol 80:17–31. https://doi.org/10.1016/j.fct.2015.02.015
Commission E (2006) Commission recommendation (EC) of 17 August 2006 on the presence of deoxynivalenol, zearalenone, ochratoxin A, T-2 and HT-2 and fumonisins in products intended for animal feeding. Off J Eur Union 229:7–9
Conkova E, Laciakova A, Kovac G, Seidel H (2003) Fusarial toxins and their role in animal diseases. Vet J 165(3):214–220
Dall’Erta A, Cirlini M, Dall’Asta M, Del Rio D, Galaverna G, Dall’Asta C (2013) Masked mycotoxins are efficiently hydrolyzed by human colonic microbiota releasing their aglycones. Chem Res Toxicol 26(3):305–312
Dellafiora L, Perotti A, Galaverna G, Buschini A, Dall’Asta C (2016) On the masked mycotoxin zearalenone-14-glucoside. Does the mask truly hide? Toxicon 111:139–142
Dellafiora L, Galaverna G, Righi F, Cozzini P, Dall’Asta C (2017) Assessing the hydrolytic fate of the masked mycotoxin zearalenone-14-glucoside—a warning light for the need to look at the “maskedome”. Food Chem Toxicol 99:9–16
Drzymala SS, Herrmann AJ, Maul R, Pfeifer D, Garbe LA, Koch M (2014) In vitro phase I metabolism of cis-zearalenone. Chem Res Toxicol 27(11):1972–1978
Drzymala SS, Binder J, Brodehl A et al (2015) Estrogenicity of novel phase I and phase II metabolites of zearalenone and cis-zearalenone. Toxicon 105:10–12
EFSA (2011) Scientific opinion on the risks for public health related to the presence of zearalenone in food. Eur Food Saf Author 9:2197–2197
EFSA (2016) Appropriateness to set a group health-based guidance value for zearalenone and its modified forms. European Food Saf Author 14:4367–4367
Freire L, Sant’Ana AS (2018) Modified mycotoxins: an updated review on their formation, detection, occurrence, and toxic effects. Food Chem Toxicol 111:189–205
Frizzell C, Uhlig S, Miles CO et al (2015) Biotransformation of zearalenone and zearalenols to their major glucuronide metabolites reduces estrogenic activity. Toxicol In Vitro 29(3):575–581
Gareis M, Bauer J, Thiem J, Plank G, Grabley S, Gedek B (1990) Cleavage of zearalenone-glycoside, a masked mycotoxin, during digestion in swine. J Vet Med B 37(3):236–240
Gratz SW, Dinesh R, Yoshinari T et al (2017) Masked trichothecene and zearalenone mycotoxins withstand digestion and absorption in the upper GI tract but are efficiently hydrolyzed by human gut microbiota in vitro. Mol Nutr Food Res. https://doi.org/10.1002/mnfr.201600680
Hess C, Ritke N, Broecker S, Madea B, Musshoff F (2013) Metabolism of levamisole and kinetics of levamisole and aminorex in urine by means of LC-QTOF-HRMS and LC-QqQ-MS. Anal Bioanal Chem 405(12):4077–4088
Hynie S, Kren V, Mraz M, Farghali H (1998) Phase I and phase II xenobiotic biotransformation in different inbred strains of rats: study in immobilized perfused hepatocytes. Folia Biol (Praha) 44(4):127–132
Kiang DT, Kennedy BJ, Pathre SV, Mirocha CJ (1978) Binding characteristics of zearalenone analogs to estrogen receptors. Cancer Res 38(11 Pt 1):3611–3615
Malekinejad H, Maas-Bakker R, Fink-Gremmels J (2006) Species differences in the hepatic biotransformation of zearalenone. Vet J 172(1):96–102
Meissen JK, Pirman DA, Wan M et al (2016) Phenotyping hepatocellular metabolism using uniformly labeled carbon-13 molecular probes and LC-HRMS stable isotope tracing. Anal Biochem 508:129–137
Meng-Reiterer J, Varga E, Nathanail AV et al (2015) Tracing the metabolism of HT-2 toxin and T-2 toxin in barley by isotope-assisted untargeted screening and quantitative LC-HRMS analysis. Anal Bioanal Chem 407(26):8019–8033
Mikula H, Weber J, Lexmuller S et al (2013) Simultaneous preparation of alpha/beta-zearalenol glucosides and glucuronides. Carbohydr Res 373:59–63
Molina-Molina JM, Real M, Jimenez-Diaz I et al (2014) Assessment of estrogenic and anti-androgenic activities of the mycotoxin zearalenone and its metabolites using in vitro receptor-specific bioassays. Food Chem Toxicol 74:233–239
Pelivan K, Frensemeier L, Karst U et al (2017) Understanding the metabolism of the anticancer drug Triapine: electrochemical oxidation, microsomal incubation and in vivo analysis using LC-HRMS. Analyst 142(17):3165–3176
Pfeiffer E, Heyting A, Metzler M (2007) Novel oxidative metabolites of the mycoestrogen zearalenone in vitro. Mol Nutr Food Res 51(7):867–871
Pfeiffer E, Hildebrand A, Mikula H, Metzler M (2010) Glucuronidation of zearalenone, zeranol and four metabolites in vitro: formation of glucuronides by various microsomes and human UDP-glucuronosyltransferase isoforms. Mol Nutr Food Res 54(10):1468–1476
Righetti L, Rolli E, Galaverna G, Suman M, Bruni R, Dall’Asta C (2017) Plant organ cultures as masked mycotoxin biofactories: deciphering the fate of zearalenone in micropropagated durum wheat roots and leaves. Plos One 12(11):e0187247
Rogiers V, Vandenberghe Y, Callaerts A et al (1990) Phase I and phase II xenobiotic biotransformation in cultures and co-cultures of adult rat hepatocytes. Biochem Pharmacol 40(8):1701–1706
Sun F, Zhang H, Gonzales GB et al (2018) Unravelling the metabolic routes of retapamulin: insights into drug development of pleuromutilins. Antimicrob Agents Chemother. https://doi.org/10.1128/AAC.02388-17
Trisciani A, Perra G, Caruso T, Focardi S, Corsi I (2012) Phase I and II biotransformation enzymes and polycyclic aromatic hydrocarbons in the Mediterranean mussel (Mytilus galloprovincialis, Lamarck, 1819) collected in front of an oil refinery. Mar Environ Res 79:29–36
Yang S, Li Y, Cao X et al (2013) Metabolic pathways of T-2 toxin in in vivo and in vitro systems of Wistar rats. J Agric Food Chem 61(40):9734–9743
Yang S, Zhang H, Sun F et al (2017a) Metabolic profile of zearalenone in liver microsomes from different species and its in vivo metabolism in rats and chickens using ultra high-pressure liquid chromatography-quadrupole/time-of-flight mass spectrometry. J Agric Food Chem 65(51):11292–11303
Yang S, De Boevre M, Zhang H et al (2017b) Metabolism of T-2 toxin in farm animals and human in vitro and in chickens in vivo using ultra high-performance liquid chromatography-quadrupole/time-of-flight hybrid mass spectrometry along with online hydrogen/deuterium exchange technique. J Agric Food Chem 65(33):7217–7227
Yang S, Van Poucke C, Wang Z, Zhang S, De Saeger S, De Boevre M (2017c) Metabolic profile of the masked mycotoxin T-2 toxin-3-glucoside in rats (in vitro and in vivo) and humans (in vitro). World Mycotoxin J 10(4):349–362
Zhou C, Zhang Y, Yin S, Jia Z, Shan A (2015) Biochemical changes and oxidative stress induced by zearalenone in the liver of pregnant rats. Hum Exp Toxicol 34(1):65–73
Zinedine A, Soriano JM, Molto JC, Manes J (2007) Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone: an oestrogenic mycotoxin. Food Chem Toxicol 45(1):1–18
Acknowledgements
This research was funded by the National Natural Science Foundation of China (no. 31702296) and the Federal Public Service of Health, Food Chain Safety and Environment (FOD) ZENDONCONVERT RT14/09 project. The authors also want to acknowledge Nathan Broekaert and Christof Van Poucke for their experienced assistance in this study.
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Yang, S., Zhang, H., Zhang, J. et al. Deglucosylation of zearalenone-14-glucoside in animals and human liver leads to underestimation of exposure to zearalenone in humans. Arch Toxicol 92, 2779–2791 (2018). https://doi.org/10.1007/s00204-018-2267-z
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DOI: https://doi.org/10.1007/s00204-018-2267-z