Trichothecenes mechanisms

Busam and Habermahl, 1982) in relatively high concentrations suggests that some plant species may be naturally resistant to the effects of macrocyclic trichothecenes. Mechanisms for such resistance have been speculated to be a rapid detoxification process within the plant cells (Jarvis et al., 1981). However baccharinoid, the macrocyclic trichothecene from Baccharis species, exhibits essentially the same degree of phytotoxicity as roridin A and E when applied to tissues of other plant species. Therefore, the vivo conversion of roridins to the baccharanoids by B, megapotomica should not be interpreted as a detoxification process (Cutler and Jarvis, 1985). 

Cundliffe, E., Cannon, M., and Davies, J. (1974). Mechanism of inhibition of eukaryotic protein synthesis b trichothecene fungal toxins. Proc. Natl. Acad. Sci. USA 71, 30-34. 

What are the mechanisms by which trichothecenes exert their transcriptional and post-transcriptional effects The 60S ribosomal subunit is a well-known molecular target of trichothecenes in leukocytes and other actively proliferating eukaryotic cells,3 whereas attempts to demonstrate alternative receptors have not been successful.37 38 Translational inhibitors that bind to ribosomes rapidly activate mitogen-activated protein kinases (MAPKs) and apoptosis via a mechanism termed the ribotoxic stress response. 39-40... 

High doses of trichothecenes promote rapid onset of leukocyte apoptosis which likely contributes to immunosuppression. DON and other trichothecenes cause apoptosis in vitro in primary T-cells, B-cells and IgA+ B cells20 as well as HL-60,53 U937 and RAW 264.7 cell lines43 via caspase-mediated mechanisms.54 These in vitro findings are relevant to the intact animal since in vivo administration of trichothecenes to rodents results in apoptosis in thymus, spleen and bone marrow.55-56 Capacity of a trichothecene to induce apoptosis corresponds to ability to inhibit translation.57... 

Pestka, J. J. et al. Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes Unraveling a paradox. Toxicol. Lett. 153, 61, 2004. 

In the first part of this chapter, we deal with insecticides including miticides and nematocides, which include very useful compounds such as avermectins and milbemycins, produced by bacteria and fungi. We list out microbial insecticides of importance and review the works mainly on the mode of action and biosynthesis of each metabolite. In the next part, major mycotoxins are listed and recent topics on them, especially on their biosynthesis, are described. Since contamination of two major mycotoxin groups, aflatoxins (AFs) and trichothecenes, in food and feed is a worldwide problem, they are treated in detail in the last part of this chapter. Recent studies on their biosynthesis, regulatory mechanism for their production, and inhibitors of their production are described. 

Proctor RH Fusarium toxins Trichothecenes and Fumonisins in Cary JW, Linz JE, Bhatnagar D (eds) Microbial Foodbome Diseases Mechanism of pathogenesis and toxin synthesis. Lancaster, Technomic Publishing 2000, pp 363—381. 

Trichothecenes are potent inhibitors of protein synthesis due to binding to the 60S ribosomal unit and this is believed to be the main mechanism of toxicity. However, recent experimental data suggest that activation of the mitogen-activated protein kinases (MAPKs) through the ribosomal stress response could be another mechanism that operates via apoptotic and proinflammatory processes. 

Some trichothecene-induced effects may be due to neurotransmitter alteration in the central nervous system. Emesis or vomiting, which occurs with many of the trichothecenes when given at high doses, has been attributed to the stimulation of the chemoreceptor trigger zone in the area postrema of the medulla oblongata. However, studies with T-2 toxin in cats indicated that other mechanisms, such as the neural afferent pathways from the abdomen, implicated in radiation-induced emesis, may also be involved (Borison and Goodheart, 1989). DON alters serotonin activity in the central nervous system of swine which is important in... 

Toxin-stimulated alteration in mitochondrial membranes contributes to the effects on cellular energetics and cellular cytotoxicity. Although initial investigations on the mechanism of action of the trichothecene mycotoxins suggested that the inhibition of protein synthesis as the principal mechanism of action, the above observations indicate that the effects of these toxins are much more diverse. 

Symptomatic measures for the treatment of exposure to trichothecene mycotoxins are modeled after the care of casualties of mustard poisoning.85 Irrigation of the eyes with large volumes of isotonic saline may assist in the mechanical removal of trichothecene mycotoxins, but would have limited useful therapeutic effects. After the skin has been decontaminated, some erythema may appear, accompanied by burning and itching. Most casualties whose skin has been treated with soap and water within 12 hours of exposure will have mild dermal effects these should be relieved by calamine and other lotion or cream, such as 0.25% camphor and methanol. 

Scheme 3. Possible cyclisation mechanisms in the biosynthesis of trichothecenes and apotrichothecenes the electronic representation is purely indicative, e.g. alcohol nucleophiles may act in their hydroxy rather than alkoxide forms...

The apotrichothecene (83) is the product from the acidcatalysed trichothecene-apotrichothecene rearrangement of 12,13-epoxytrichothe-cene (73) and could be an artefact. The 12-epi-apotrichothecene (100) is believed to arise from the hypothetical intermediate 11-epiisotrichodiol (143 Scheme 3), and by mechanism E (228) which involves epoxideopening with retention of configuration. Isotrichodiol and its 11-epimer should be interconvertible via the common allylic cation. 

The nature of the biosynthetic pathway to sambucinol (81) is controversial. Trichodiene and isotrichool (52) are proven precursors in F. culmorum (225), as are apotrichool (85) (226) and 3-deoxysambucinol (80) (285). Another precursor is 2a,13-dihydroxyapotrichothecene (84) (227), which has not yet been isolated as a natural product but which should be readily obtainable from 11-epiisotrichodiol (143) by mechanism F, Scheme 3. Apotrichodiol (86) is converted photochemically in solution at room temperature into the acetal (92) (211), a likely precursor of sporol (91). Similar photochemical reactions with 2a-hydroxyapo-trichothecenes, which could lead to deoxysambucinol (80) (mechanism F), have not been reported. 

Kimura M, Shingu Y, Yoneyama K, Yamaguchi I (1998) Features of TrilOl, the Trichothecene 3-O-Acetyltransferase Gene, Related to the Self-Defense Mechanism in Fusarium graminearum. Biosci Biotechnol Biochem 62 1033... 

Feinberg, B. McLaughlin, C.S. (1989). Biochemical mechanism of action of trichothecene mycotoxins. In Tridtotitecene mycotoxicosis pathophysiologic effects 1, Beasley, V.R., pp. 32-33, CRC Press, ISBN 0-8493-5088-3, Boca Raton, FL, USA. 

In summary, in depth-exploration of the concept of modifying active sites of trichothecenes both in vitro and in vivo to prevent them from interacting with living cells will not only contribute to our understanding of basic mechanisms of trichothe-cene toxicity at the molecular level, but also should lead to the discovery of new ways to treat contaminated foods and people and to the development of new prophylactic and therapeutic compounds. 

Trichothecene mycotoxins inhibit DNA and RNA nucleic acid synthesis. Fligher dosages are required to inhibit nucleic acid synthesis than to inhibit protein synthesis, implying that a different mechanism may be operative for each efiect. 

Trichothecenes are directly cytotoxic to a variety of cells in vitro. The mechanism is unclear, but direct cytotoxicity may explain the dermonecralic effects repotted for trichothecenes. 

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