Trichothecenes protein synthesis inhibition

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. 

Azcona-Olivera, J. I. et al. Induction of cytokine mRNAs in mice after oral exposure to the trichothecene vomitoxin (deoxynivalenol) Relationship to toxin distribution and protein synthesis inhibition. Toxicol. Appl. Pharmacol. 133, 109, 1995. 

Some biological effects may be mediated by reaction of the epoxy groups of trichothecenes with sulfhydryl groups on enzymes and binding of certain trichothecenes to membrane components. T-2 toxin rapidly affected glucose, nucleotide and amino acid transporters as well as calcium/ potassium channel activities in vitro indicating alteration of cell membrane functions independent of protein synthesis inhibition (Brunner and Morris, 1988). In pigs, DAS was... 

The toxic efiects of the 12,13-epoxytrichothecenes are associated with the more highly oxidized members such as T-2 toxin (9.8) and vomitoxin (deoxynivalenol) (9.6) together with their macrocychc esters. The symptoms of alimentary toxic aleukia in test animals (cats) were detected on administration of T-2 toxin at a level of 0.08 mg kg per day. Structure activity studies on T-2 toxin revealed a requirement for the presence of the 12,13-epoxide and the 9-ene. The compounds exert their activity by the inhibition of protein synthesis. The trichothecenes interfere with the peptidyl transferase in the ribosomes. 

McLaughlin CS, Vaughan MH, Campbell IM, Wei CM, Stafford ME, Hansen BS. Inhibition of protein synthesis by trichothecenes. In Rodericks JV, Hesseltine CW, Mehlman MA, eds. Mycotoxins in Human and Animal Health. Park Forest South, Ill Pathotox Publishers 1977 263-275. 

McLaughlin, C.S. et al. (1977). Inhibition of protein synthesis by trichothecenes. In "Mycotoxins in Human and Animal Health", O.V. Rodricks, C.W. Hesseltine, and M.A. Mehlman, Eds., p. 363-373, Pathotox Publishers, Park Forest, Illinois. 

CuNDLiFFE, E., and J. E. Davies Inhibition of initiation, elongation and termination of eukaryotic protein synthesis by trichothecene fungal toxins. Antimicrob. Agents Chemother. 11, 491 (1977). 

Trichothecene mycotoxin Toxin produced by fungal molds it inhibits protein synthesis, impairs DNA synthesis, and interferes with cell membrane structure and function. 

Trichothecene mycotoxins are produced by a number of fungal molds of the Fusarium, Myrotecium, Trichoderma, and Stachybotrys genera. They inhibit protein synthesis, impair DNA synthesis, and interfere with cell membrane structures and functions. The potential routes of exposure are inhalation, ingestion, and skin absorption. A terrorist may take advantage of any of these routes. 

Trichothecenes can be divided into two groups based on their site of action on protein synthesis. Trichothecenes with hydroxyl and acetyl substitutions at both C-3 and C-4, such as T-2 toxin, DAS, verrucarin A, preferentially inhibit initiation while DON, trichodermin, crotocin, and verucarol inhibit elongation and/or termination (McLaughlin et al, 1977). Trichothecenes inhibit both DNA and RNA synthesis... 

In protozoa, Tetrahymena pyriformis trichothecene, such as T-2. toxin and Fusarenon-X, also inhibit DNA syntheses along with protein synthesis. Also, dis-... 

Several studies investigated the in vivo toxicity of macrocyclic trichothecenes [135], It is assumed that their toxic effects are based on the inhibition of protein synthesis, with a slowly progressing respiratory depression and paralysis of skeletal muscles. The epidermal remains of these plant species that produce acute intoxication in rumiants were also quantified by microhistological analysis in the gastrointestinal content of sheep which had been experimentally poisoned [136]. 

Some trichothecenes, a group of mycotoxins, have macrodiolide or macrotri-olide skeletons. Trichothecenes inhibited protein synthesis by binding to the ribosomal peptidyltransferase site [141]. Roritoxins (roritoxin A, 113) are 16-membered ring macrodiolides isolated from Myrothecium roridum [142]. Verru-carin A (114) is an 18-membered ring macrotriolide produced by Myrothecium spp. [143]. 

Substantial inhibition of ribonucleic acid (RNA) synthesis (86% inhibition) by trichothecene myco-toxin was observed in human (HeLa) cells,47 but T-2 toxin had minor effects (15% inhibition) on RNA synthesis in Vero cells.46 The trichothecene myco-toxin-related inhibition of RNA synthesis is probably a secondary effect of the inhibition of protein synthesis. Scheduled DNA synthesis is strongly inhibited in various types of cells that are exposed to trichothecene mycotoxins. In mice or rats treated with trichothecene mycotoxins, DNA synthesis in all tissues studied was suppressed, although to a lesser degree than protein synthesis.49 The pattern by which DNA synthesis is inhibited by the trichothecene mycotoxins is consistent with the primary effect of these toxins on protein synthesis. In appropriate cell models, for the most part, trichothecene mycotoxins demonstrate neither mutagenic activity nor the capacity to damage DNA.50... 

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. 

Compared with some of the other mycotoxins such as aflatoxin, the trichothecenes do not appear to require metabolic activation to exert their biological activity.50 After direct dermal application or oral ingestion, the trichothecene mycotoxins can cause rapid irritation to the skin or intestinal mucosa. In cell-free systems or single cells in culture, these mycotoxins cause a rapid inhibition of protein synthesis and polyribosomal disaggregation.35 47 50 Thus, we can postulate that the trichothecene mycotoxins have molecular capability of direct reaction with cellular components. Despite this direct effect, it is possible to measure the toxicokinetics and the metabolism of the trichothecene mycotoxins. 

Casale, W. L. Inhibition of protein synthesis in maize and wheat by trichothecene mycotoxins and hybridoma-based enzyme immunoassay for deoxynivalenol. 168 pp. Avail. Univ. Microfilms Int., Order No. DA8722822. From Diss. Abstr. Int B 1988,48(8), 2167. 1987. 

Trichothecenes bind to eukaryotic ribosomes and inhibit protein synthesis (Pestka, Zhou, Moon, Chung, 2004). Different trichothecenes interfere with initiation, elongation and termination stages of protein synthesis. They are also immunosuppressive. Acute trichothecene mycotoxicosis are rare, but when ingested in high doses by farm animals they cause nausea, vomiting and diarrhea. DON is also called a vomitoxin or food refusal factor (Bennett Klich, 2003). Trichothecenes are not classifiable as to their carcinogenicity to humans (Class 3) (lARC). 

Trichothecenes are potent inhihitors of protein synthesis in mammalian cells, reportedly by degrading polyribosomes and inhibiting the initiation phase of protein synthesis. T-2 toxin has a high affinity for 60S ribosomal subunits, which may explain its effects on protein synthesis. 

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. 

Low dosages of trichothecenes inhiiit membrane transfer of gkjcosr, ciddum, and some amino acids in vitro. These effects are indeperxlent of the inhibition of protein synthesis. 

Ueno, Y., Nakajima, N., Sakai, K., Ishii, K., Sato, N. and Shimada, N. 1973. Comparative toxicology of trichothecene mycotoxins inhibition of protein synthesis in animal cells. J. Biochem. 74 285-296. 

The most recent model study, undertaken by Trost and McDougal, has explored an unusual approach to verrucarin-type trilactides 148). Their supposition was that thermal isomerization of the cw-cyclobutene (242), which could produce two possible. Z-isomers by competing conrotatory processes, would exhibit selectivity due to the conformational constraint imposed by the macrocycle. The synthesis of the target molecule is outlined in Scheme 29. Importantly, the key macrolactonization (241->-242) proceeded without isomerization of the cw-cyclobutene moiety. Upon thermolysis a mixture of. Z-isomers (243) and (244) was obtained. Comparison with an authentic sample revealed that the natural isomer (243) was indeed the major compound present (2 1). The applicability of such an approach to the verrucarins must yet be explored. Interestingly, these relatively simple models inhibit protein synthesis in a fashion reminiscent of the natural trichothecenes. 

TRICHOTHECENE MYCOTOXINS. A family of structurally related poisonous substances produced by various species of fungi, especially Acremorium (Cephalosporium), Fusarium, Myrothe-cium, Stachybotrys, Trichderme, and Verticumonosporium. Tri-chothecene mycotoxins are toxic to humans because they inhibit cellular protein synthesis. Prominent examples are deoxynivalenol (sometimes referred to as vomitoxin because it induces vomiting), diacetoxyscirpenol, HT-2, nivalenol, and T-2. These five toxins gained some notoriety in the so-caUed yellow rain events in Southeast Asia because of allegations that they were associated with Soviet-inspired use of chemical weapons (CW). 

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