Deoxynivalenol (DON) and its modified forms, including DON-3-glucoside (DON-3G), pose a major agricultural and food safety issue in the world. Their metabolites are relatively well-characterized; however, their metabolizing enzymes have not been fully explored. UDP-glucuronosyltransferases, 3-O-acetyltransferase, and glutathione S-transferase are involved in the formation of DON-glucuronides, 3-acetyl-DON, and DON-glutathione, respectively. There are interindividual differences in the metabolism of these toxins, including variation with respect to sex. Furthermore, interspecies differences in DON metabolism have been revealed, including differences in the major metabolites of DON, the role of de-acetylation, and the hydrolysis of DON-3G. In this review, we summarized the major enzymes involved in metabolizing DON to its modified forms, focusing on the differences in metabolism of DON and its modified forms between individuals and species. This work provides important insight into the toxicity of DON and its derivatives in humans and animals, and provides scientific basis for the development of safer and more efficient biological detoxification methods.
- MeSH
- glukuronidy metabolismus MeSH
- glukuronosyltransferasa metabolismus MeSH
- hydrolýza MeSH
- lidé MeSH
- metabolická inaktivace * MeSH
- trichotheceny * chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G's emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend® restrained the induction of emesis by SP and D3G. Importantly, CaSR antagonist NPS-2143 or TRP channel antagonist ruthenium red dose-dependently inhibited both D3G-induced emesis and brain-gut peptides GIP and SP release; cotreatment with both antagonists additively suppressed both emetic and brain-gut peptide responses to D3G. To summarize, our findings demonstrate that activation of CaSR and TRP channels contributes to D3G-induced emesis by mediating brain-gut peptide exocytosis in mink.
- MeSH
- emetika * toxicita MeSH
- glukosa MeSH
- glukosidy MeSH
- norek MeSH
- receptory gastrointestinálních hormonů MeSH
- receptory spřažené s G-proteiny MeSH
- substance P MeSH
- trichotheceny * chemie toxicita MeSH
- zvířata MeSH
- zvracení chemicky indukované MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Paradoxically, trichothecenes have both immunosuppressive and immunostimulatory effects. The underlying mechanisms have not been fully explored. Early studies show that dose, exposure timing, and the time at which immune function is assessed influence whether trichothecenes act in an immunosuppressive or immunostimulatory fashion. Recent studies suggest that the immunomodulatory function of trichothecenes is also actively shaped by competing cell-survival and death-signaling pathways. Autophagy may also promote trichothecene immunosuppression, although the mechanism may be complicated. Moreover, trichothecenes may generate an "immune evasion" milieu that allows pathogens to escape host and vaccine immune defenses. Some trichothecenes, especially macrocyclic trichothecenes, also potently kill cancer cells. T-2 toxin conjugated with anti-cancer monoclonal antibodies significantly suppresses the growth of thymoma EL-4 cells and colon cancer cells. The type B trichothecene diacetoxyscirpenol specifically inhibits the tumor-promoting factor HIF-1 in cancer cells under hypoxic conditions. Trichothecin markedly inhibits the growth of multiple cancer cells with constitutively activated NF-κB. The type D macrocyclic toxin Verrucarin A is also a promising therapeutic candidate for leukemia, breast cancer, prostate cancer, and pancreatic cancer. The anti-cancer activities of trichothecenes have not been comprehensively summarized. Here, we first summarize the data on the immunomodulatory effects of trichothecenes and discuss recent studies that shed light on the underlying cellular and molecular mechanisms. These mechanisms include autophagy and major signaling pathways and their crosstalk. Second, the anti-cancer potential of trichothecenes and the underlying mechanisms will be discussed. We hope that this review will show how trichothecene bioactivities can be exploited to generate therapies against pathogens and cancer.
- MeSH
- antikarcinogenní látky farmakologie MeSH
- autofagie účinky léků imunologie MeSH
- imunoglobulin A imunologie MeSH
- imunologické faktory farmakologie MeSH
- imunosupresiva farmakologie MeSH
- infekce farmakoterapie imunologie MeSH
- lidé MeSH
- signální transdukce účinky léků imunologie MeSH
- trichotheceny chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Enzyme-linked immunosorbent assay (ELISA) represents a bioanalytical strategy frequently used for rapid screening of mycotoxin deoxynivalenol (DON) in cereals and derived products. Due to a considerable affinity of some anti-DON antibodies to structurally similar DON metabolites, such as DON-3-glucoside (DON-3-Glc) and 3-acetyl-DON (3-ADON), a significant overestimation of DON concentrations may occur. A validation study of six commercial DON-dedicated ELISA kits, namely Ridascreen DON, Ridascreen FAST, DON, DON EIA, AgraQuant DON Assay, Veratox 5/5, and Veratox HS was carried out on wheat, barley, and malt matrices. Performance characteristics of all tested ELISAs were determined using aqueous solutions of DON, DON-3-Glc, and 3-ADON analytical standards, further with extracts of artificially spiked blank cereals, and finally with matrix-matched standards of all three compounds. In the final phase, the accuracy of data was assessed through a comparison of DON concentrations determined by particular ELISAs and reference ultra-high-performance liquid chromatography-tandem mass spectrometry method. For this purpose, both quality control materials and a comprehensive set of naturally and artificially contaminated samples of wheat, barley, and malt were analyzed. High cross-reactivities were proved for both DON-3-Glc and 3-ADON in the majority of examined assays, and moreover, a considerable contribution of some matrix components to overestimation of DON results was confirmed.
- MeSH
- artefakty * MeSH
- ELISA normy MeSH
- glukosidy chemie MeSH
- ječmen (rod) chemie mikrobiologie MeSH
- mykotoxiny analýza MeSH
- protilátky chemie MeSH
- pšenice chemie mikrobiologie MeSH
- reagenční diagnostické soupravy normy MeSH
- specificita protilátek MeSH
- tandemová hmotnostní spektrometrie MeSH
- trichotheceny analýza chemie MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Pro organismus člověka představují mykotoxiny významné zdravotní riziko, které je potřeba řídit, tj. minimalizovat jeho dopady na lidské zdraví. Biologické účinky mykotoxinů jsou podmíněné jejich rozdílnou chemickou strukturou. K významným patří např. také skupina tzv. epoxytrichotecenů, např. DON, DAS (diacetoxyscirpenol), nivalenol, T-2 toxin, fusarenony, satratoxiny, roridiny, verukariny aj., kterých bylo popsáno více než 170. Rozhodujícími faktory toxického účinku mykotoxinů obecně, tedy i trichotecenů, jsou dávka a délka doby jejich působení (velikost expozice), individuální citlivost, věk, pohlaví, zdravotní stav a stav výživy, vitaminová deficience, abúzus alkoholu a infekční onemocnění. Kombinace dvou či více současně se vyskytujících tzv. „emerging“ (vznikajících) mykotoxinů či tzv. „maskovaných“ mykotoxinů v surovinách i potravinách může v důsledku synergického spolupůsobení (při uvažované dietární expozici) působit mnohem toxičtěji. Za toxikologicky významné trichoteceny jsou považovány např. deoxynivalenol (DON) a T-2 toxin (jehož limit v potravinách v EU je stále diskutovaným a nedořešeným problémem), z dalších by si zasloužil regulaci také např. hematotoxický nivalenol aj. Zcela nepochybně by se v této skupině našla celá řada dalších, zasluhujících pozornost. Pro svoji toxicitu a možné zneužití jsou (epoxy)trichoteceny v ČR v působnosti zákona č. 281/2002 Sb. a jeho prováděcí vyhlášky č. 474/2002 Sb., o některých opatřeních souvisejících se zákazem bakteriologických (biologických) a toxinových zbraní. Záměrem této práce je proto sledování některých toxických účinků vybraných epoxytrichotecenů.
In the human organism, mycotoxins present a considerable risk, which must be controlled, i.e. its impact on the human health should be minimized. Biological effects of mycotoxins are associated with their different chemical structures. Important mycotoxins also include a group of so called epoxytrichothecenes, as for example DON, DAS (diacetoxyscirpenol), nivalenol, T-2 toxin, fusarenons, satratoxins, roridins, verrucarins, etc. which have been described in a number exceeding 170. The decisive factors determining toxic effects of mycotoxins in general, and thus also of trichothecenes, are their dose and time period of their action (the magnitude of the exposure), individual sensitivity, age, gender, condition of health and nutrition, vitamin deficiency, alcohol abuse and infectious diseases. Combinations of two or more so called “emerging” or “masked” mycotoxins concomitantly occurring in foodstuffs and/or raw materials can, as a result of their synergism (at a dietary exposure considered), induce much higher toxic effects. Toxicologically important mycotoxins are trichothecenes as for example deoxynivalenol (DON) and T-2 toxin (its limit concentrations being a still discussed and yet not solved problem in the EU); regulation should also be considered for haematotoxic nivalenol, etc. Appropriate attention should also be undoubtedly paid to a number of further species. Due to their toxicity and possible abuse, in the Czech Republic, (epoxy)trichothecenes are subjected to the force of Law No. 281/2002 Sb and its executing Regulation No. 474/2002 Sb. “On some provisions associated with the prohibition of bacteriological (biological) and toxin weapons”. The purpose of the work presented here is thus monitoring of certain toxic effects of selected epoxytrichothecenes.
The co-occurrence of deoxynivalenol-3-glucoside with its parent toxin, deoxynivalenol, has been recently documented in many cereal-based foods, especially in those produced by enzyme-catalyzed processes. The presence of this masked mycotoxin in the human diet has become an issue of health concern, mainly because of its assumed bioavailability. A selective immunoaffinity-based preconcentration strategy, followed by ultrahigh-performance liquid chromatography coupled with high-resolution orbitrap mass spectrometry, revealed that, in addition to the most common deoxynivalenol-3-glucoside, also oligoglycosylated deoxynivalenols with up to four bound hexose units were present in cereal-based products. The structure, origination, and fate of these deoxynivalenol conjugates during malt/beer production and bread baking have been thoroughly investigated. Special attention has been paid to the changes of deoxynivalenol conjugates enabled by industrial glycosidase-based enzymatic preparations. To the authors' best knowledge, this is the first study documenting the complexity of masked deoxynivalenol issue.
- MeSH
- chléb analýza MeSH
- Fusarium metabolismus MeSH
- glukosidy chemie MeSH
- jedlá semena chemie MeSH
- kontaminace potravin analýza MeSH
- molekulární struktura MeSH
- mykotoxiny chemie metabolismus MeSH
- pivo analýza MeSH
- trichotheceny chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
