Abstract
Zearalenone (ZEN) is a mycotoxin produced by Fusarium species. ZEN mainly appears in cereals and related foodstuffs, causing reproductive disorders in animals, due to its xenoestrogenic effects. The main reduced metabolites of ZEN are α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL). Similarly to ZEN, ZELs can also activate estrogen receptors; moreover, α-ZEL is the most potent endocrine disruptor among these three compounds. Serum albumin is the most abundant plasma protein in the circulation; it affects the tissue distribution and elimination of several drugs and xenobiotics. Although ZEN binds to albumin with high affinity, albumin-binding of α-ZEL and β-ZEL has not been investigated. In this study, the complex formation of ZEN, α-ZEL, and β-ZEL with human (HSA), bovine (BSA), porcine (PSA), and rat serum albumins (RSA) was investigated by fluorescence spectroscopy, affinity chromatography, thermodynamic studies, and molecular modeling. Our main observations are as follows: (1) ZEN binds with higher affinity to albumins than α-ZEL and β-ZEL. (2) The low binding affinity of β-ZEL toward albumin may result from its different binding position or binding site. (3) The binding constants of the mycotoxin-albumin complexes significantly vary with the species. (4) From the thermodynamic point of view, the formation of ZEN-HSA and ZEN-RSA complexes are similar, while the formation of ZEN-BSA and ZEN-PSA complexes are markedly different. These results suggest that the toxicological relevance of ZEN-albumin and ZEL-albumin interactions may also be species-dependent.
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References
Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E (2015) GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1:19–25. https://doi.org/10.1016/j.softx.2015.06.001
Chruszcz M, Mikolajczak K, Mank N, Majorek KA, Porebski PJ, Minor W (2013) Serum albumins—unusual allergens. Biochim Biophys Acta 1830:5375–5381. https://doi.org/10.1016/j.bbagen.2013.06.016
European Food Safety Authority (EFSA) (2017) Risks for animal health related to the presence of zearalenone and its modified forms in feed. EFSA J 15:4851. https://doi.org/10.2903/j.efsa.2017.4851
Fanali G, Di Masi A, Trezza V, Marino M, Fasano M, Ascenzi P (2012) Human serum albumin: from bench to bedside. Mol Asp Med 33:209–290. https://doi.org/10.1016/j.mam.2011.12.002
Filannino A, Stout TA, Gadella BM, Sostaric E, Pizzi F, Colenbrander B, Dell'Aquila ME, Minervini F (2011) Dose-response effects of estrogenic mycotoxins (zearalenone, alpha- and beta-zearalenol) on motility, hyperactivation and the acrosome reaction of stallion sperm. Reprod Biol Endocrinol 9:134. https://doi.org/10.1186/1477-7827-9-134
Fleck SC, Churchwell MI, Doerge DR (2017) Metabolism and pharmacokinetics of zearalenone following oral and intravenous administration in juvenile female pigs. Food Chem Toxicol 106:193–201. https://doi.org/10.1016/j.fct.2017.05.048
Frizzell C, Ndossi D, Verhaegen S, Dahl E, Eriksen G, Sørlie M, Ropstad E, Muller M, Elliott CT, Connolly L (2011) Endocrine disrupting effects of zearalenone, alpha- and beta-zearalenol at the level of nuclear receptor binding and steroidogenesis. Toxicol Lett 206:210–217. https://doi.org/10.1016/j.toxlet.2011.07.015
Gans P, Sabatini A, Vacca A (1996) Investigation of equilibria in solution. Determination of equilibrium constants with the HYPERQUAD suite of programs. Talanta 43:1739–1753. https://doi.org/10.1016/0039-9140(96)01958-3
Hetényi C, van der Spoel D (2002) Efficient docking of peptides to proteins without prior knowledge of the binding site. Protein Sci 11:1729–1737. https://doi.org/10.1110/ps.0202302
Hetényi C, van der Spoel D (2006) Blind docking of drug-sized compounds to proteins with up to a thousand residues. FEBS Lett 580:1447–1450. https://doi.org/10.1016/j.febslet.2006.01.074
Hetényi C, van der Spoel D (2011) Toward prediction of functional protein pockets using blind docking and pocket search algorithms. Protein Sci 20:880–893. https://doi.org/10.1002/pro.618
Huang LC, Zheng N, Zheng BQ, Wen F, Cheng JB, Han RW, Xu XM, Li SL, Wang JQ (2014) Simultaneous determination of aflatoxin M1, ochratoxin A, zearalenone and α-zearalenol in milk by UHPLC-MS/MS. Food Chem 146:242–249. https://doi.org/10.1016/j.foodchem.2013.09.047
Kaspchak E, Mafra LI, Mafra MR (2018) Effect of heating and ionic strength on the interaction of bovine serum albumin and the antinutrients tannic and phytic acids, and its influence on in vitro protein digestibility. Food Chem 252:1–8. https://doi.org/10.1016/j.foodchem.2018.01.089
Kőszegi T, Poór M (2016) Ochratoxin A: molecular interactions, mechanisms of toxicity and prevention at the molecular level. Toxins 8:111. https://doi.org/10.3390/toxins8040111
Li Y, Wang H, Jia B, Liu C, Liu K, Qi Y, Hu Z (2013) Study of the interaction of deoxynivalenol with human serum albumin by spectroscopic technique and molecular modelling. Food Addit Contam Part A 30:356–364. https://doi.org/10.1080/19440049.2012.742573
Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE (2010) Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 78:1950–1958. https://doi.org/10.1002/prot.22711
Ma L, Maragos CM, Zhang Y (2018) Interaction of zearalenone with bovine serum albumin as determined by fluorescence quenching. Mycotoxin Res 34:39–48. https://doi.org/10.1007/s12550-017-0297-7
Maragos CM (2010) Zearalenone occurrence and human exposure. World Mycotoxin J 3:369–383. https://doi.org/10.3920/WMJ2010.1240
Minervini F, Dell’Aquila ME (2008) Zearalenone and reproductive function in farm animals. Int J Mol Sci 9:2570–2584. https://doi.org/10.3390/ijms9122570
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791. https://doi.org/10.1002/jcc.21256
Perry JL, Il’ichev YV, Kempf VR, McClendon J, Park G, Manderville RA, Rüker F, Dockal M, Simon JD (2003) Binding of ochratoxin A derivatives to human serum albumin. J Phys Chem B 107:6644–6647. https://doi.org/10.1021/jp034284w
Poór M, Kunsági-Máté S, Bencsik T, Petrik J, Vladimir-Kneževic S, Kőszegi T (2012) Flavonoid aglycones can compete with ochratoxin A for human serum albumin: a new possible mode of action. Int J Biol Macromol 51:279–283. https://doi.org/10.1016/j.ijbiomac.2012.05.019
Poór M, Li Y, Matisz G, Kiss L, Kunsági-Máté S, Kőszegi T (2014) Quantitation of species differences in albumin-ligand interactions for bovine, human and rat serum albumins using fluorescence spectroscopy: a test case with some Sudlow's site I ligands. J Lumin 145:767–773. https://doi.org/10.1016/j.jlumin.2013.08.059
Poór M, Lemli B, Bálint M, Hetényi C, Sali N, Kőszegi T, Kunsági-Máté S (2015) Interaction of citrinin with human serum albumin. Toxins 7:5155–5166. https://doi.org/10.3390/toxins7124871
Poór M, Bálint M, Hetényi C, Gődér B, Kunsági-Máté S, Kőszegi T, Lemli B (2017a) Investigation of non-covalent interactions of aflatoxins (B1, B2, G1, G2, and M1) with serum albumin. Toxins 9:339. https://doi.org/10.3390/toxins9110339
Poór M, Kunsági-Máté S, Bálint M, Hetényi C, Gerner Z, Lemli B (2017b) Interaction of mycotoxin zearalenone with human serum albumin. J Photochem Photobiol B 170:16–24. https://doi.org/10.1016/j.jphotobiol.2015.07.009
Poór M, Boda G, Kunsági-Máté S, Needs PW, Kroon PA, Lemli B (2018) Fluorescence spectroscopic evaluation of the interactions of quercetin, isorhamnetin, and quercetin-3′-sulfate with different albumins. J Lumin 194:156–163. https://doi.org/10.1016/j.jlumin.2017.10.024
Ross PD, Subramanian S (1981) Thermodynamics of protein association reactions: forces contributing to stability. Biochemistry 20:3096–3102. https://doi.org/10.1021/bi00514a017
Schollenberger M, Müller HM, Rüfle M, Suchy S, Plank S, Drochner W (2006) Natural occurrence of 16 fusarium toxins in grains and feedstuffs of plant origin from Germany. Mycopathologia 161:43–52. https://doi.org/10.1007/s11046-005-0199-7
Schrödinger LLC (2013) Schrödinger release 2013–3: SiteMap, Version 2.9. Schrödinger, LLC, New York
Shier WT, Shier AC, Xie W, Mirocha CJ (2001) Structure-activity relationships for human estrogenic activity in zearalenone mycotoxins. Toxicon 39:1435–1438. https://doi.org/10.1016/S0041-0101(00)00259-2
Stewart JJ (1990) MOPAC: a semiempirical molecular orbital program. J Comput Aided Mol Des 4(1):105
Sueck F, Poór M, Faisal Z, Gertzen CGW, Cramer B, Lemli B, Kunsági-Máté S, Gohlke H, Humpf HU (2018) Interaction of ochratoxin A and its thermal degradation product 2'R-ochratoxin A with human serum albumin. Toxins 10:E256. https://doi.org/10.3390/toxins10070256
Yamasaki K, Chuang VT, Maruyama T, Otagiri M (2013) Albumin-drug interaction and its clinical implication. Biochim Biophys Acta 1830:5435–5443. https://doi.org/10.1016/j.bbagen.2013.05.005
Yazar S, Omurtag GZ (2008) Fumonisins, trichothecenes and zearalenone in cereals. Int J Mol Sci 9:2062–2090. https://doi.org/10.3390/ijms9112062
Yuqin L, Guirong Y, Zhen Y, Caihong L, Baoxiu J, Jiao C, Yurong G (2014) Investigation of the interaction between patulin and human serum albumin by a spectroscopic method, atomic force microscopy, and molecular modeling. Biomed Res Int 2014:734850. https://doi.org/10.1155/2014/734850
Zsila F (2013) Subdomain IB is the third major drug binding region of human serum albumin: toward the three-sites model. Mol Pharm 10:1668–1682. https://doi.org/10.1021/mp400027q
Acknowledgements
This project was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (M.P.). M.P. is thankful for support of the University of Pécs for grant in the frame of Pharmaceutical Talent Centre program. This work was supported by the GINOP-2.3.2-15-2016-00049 grant. We acknowledge a grant of computer time from CSCS Swiss National Supercomputing Centre, and NIIF Hungarian National Information Infrastructure Development Institute. We acknowledge that the results of this research have been achieved using the DECI resource Archer based in the UK at the National Supercomputing Service with support from the PRACE aisbl. M.B. and C.H. are thankful to the University of Pécs for the grant in the frame of “Supporting Individual Research and Innovation Activity of Young Researchers, 2018” program.
Funding
This project was supported by the Hungarian National Research, Development and Innovation Office (FK125166) (M.P.). The work of M.B. and C.H. is supported by the Hungarian National Research, Development and Innovation Office (K123836).
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Faisal, Z., Lemli, B., Szerencsés, D. et al. Interactions of zearalenone and its reduced metabolites α-zearalenol and β-zearalenol with serum albumins: species differences, binding sites, and thermodynamics. Mycotoxin Res 34, 269–278 (2018). https://doi.org/10.1007/s12550-018-0321-6
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DOI: https://doi.org/10.1007/s12550-018-0321-6