Metabolism trichothecenes

Soil microorganisms produce many compounds that are potentially toxic to higher plants. Examples include members of the following antibiotics (1-6), fatty and phenolic acids (7-12), amino compounds (13-15), and trichothecenes (16, 17). "Soil sickness" and "replant problems" have been reported where certain crops or their residues interfere with establishment of a subsequent crop (18, 19). Toxins resulting from microbial activity sometimes are involved, but it is often unclear whether these are synthesized de novo in microbial metabolism or are breakdown products of the litter itself (20). 

Ex vivo studies have revealed that trichothecenes can both inhibit and stimulate leukocyte function.12 For example, trichothecenes are toxic to alveolar macrophages,13 but drive differentiation of human myeloid leukemic cells.14 Dose-dependent decreases or increases in B- and T-cell mitogen responses are observable in lymphocytes from animals exposed to T-2 toxin, DON, or various macrocyclic trichothecenes these toxins similarly impair or enhance mitogen-induced lymphocyte proliferation in vitro.12 Rank order of inhibitor potency in rodent and human lymphocyte proliferation assays is Type D > Type A group > Type B group and is dependent on degree of acylation as well as of uptake and metabolism. 

Swanson, S.P. et ah. Metabolism of three trichothecene mycotoxins, T-2 toxin, diacetoxyscirpenol and deox5mivalenol, by bovine rumen microorganisms, J. Chromatogr., 414, 335, 1987. 

Contamination occurs primarily in wheat, barley, rye, and maize. Type A trichothecenes include mainly T-2 toxin, HT-2, and diacetoxyscirpenol (DAS) mycotoxins of the group B include mainly 4-deoxynivalenol (DON), commonly known as vomitoxin, and nivalenol (NIV). Toxic effects include nausea, vomiting, visual disorder, vertigo, throat irritation, and feed refusal in farm animals. The most toxic is T-2, followed by DAS and NIV, with DON being the least toxic in acute toxicity studies but the most widespread in grains worldwide and therefore the most studied. Issues related to chemical and physical data, occurrence, toxicity, absorption, distribution, and metabolism of trichothecenes are reviewed in WHO (89) and IARC (34). Physicochemical data for some selected Fusarium toxins is given by Sydenham et al. (90). The molecular structures of the main trichothecenes are shown in Fig. 9. 

Mycotoxins are, in general, low molecular weight, non-antigenic fungal secondary metabolites formed by way of several metabolic pathways, e.g. the polyketide route (aflatoxins), the terpene route (trichothecenes), the amino acid... 

Trichothecene 3-O-acetyltransferase encoded by a noncluster gene, TrilOl, readily converts isotrichodermol (130) into isotrichodermin (ITD, 131) (Figure 30).262 263 This acetylation step is important for the selfprotection of trichothecene-producing Fusarium species. The C-3 acetyl is also essential for subsequent biosynthetic steps to proceed. Indeed, the 7W/0/--targeted gene disruption mutant of F. sporotrichioides could not metabolize 3-hydroxytrichothecenes, but efficiently converted exogenously added ITD (131) and other C-3 acetylated intermediates into T-2 toxin.264 After ITD (131), the biosynthetic pathways are different between type A and type B trichothecenes. 

Figure 31 Biosynthesis of type A trichothecenes. ITD (131) is metabolized to T-2 toxin along the biosynthetic grids. Either C-8 hydroxylation or C-4 hydroxylation of CAL (133) may occur.

In fungal species such as Myrothecium roridum and T. roseum, ITdiol (128) is subsequently cyclized to EPT, a minimum trichothecene skeleton also given a specific compound name trichothecene (Figure 33). EPT is a precursor specific to non-Fusarium trichothecenes because it is not metabolized to Fusarium trichothecenes (that have an acetyl or a hydroxyl at C-3) by trichothecene-producing Fusarium species.276 This implies that the determinant of Fusarium trichothecene and non-Fusarium trichothecene is the functional difference of Tri4 that functions between the first and second cyclizations in the biosynthetic pathways. 

Schiefer, H.B., Beasley, V.R. (1989). Effects on the digestive system and energy metabolism. In Trichothecene Mycotox-icosis Pathophysiological Effects, Vol. II (V.R. Beasley, ed.), pp. 61-90. CRC Press, Boca Raton, FL. 

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. 

Pharmacokinetic studies60,61 have demonstrated T-2 toxin in the plasma of animals that were administered this mycotoxin both intravascularly and by aerosol. As plasma concentrations of the parent trichothecene mycotoxin decrease, the deacylated and hydroxylated metabolites and their glucu-ronide conjugates rapidly appear and disappear from circulation. From these various observations, we can conclude that the pharmacokinetics of the trichothecene mycotoxins are functions of the rate of absorption into the general circulation, metabolism, tissue distribution, and excretion. 

Regardless of the route of administration or the species of animal tested, the trichothecene mycotoxins were rapidly metabolized and excreted in urine... 

Four hours after swine received intravenous tritium-labeled T-2 toxin, glucuronide conjugates represented 63% of the metabolic residues in urine, and 77% in bile.63 The formation of glucuronide conjugates generally results in the elimination of toxicological activity of xenobiotics, which in certain species could represent a major route of detoxification of trichothecene mycotoxins. 

Swanson SP, Helaszek C, Buck WB, Rood HDJ, Haschek WM. The role of intestinal microflora in the metabolism of trichothecene mycotoxins. Food Chem Toxicol. 1988 26(10) 823-830. 

Yagen B, Bialer M. Metabolism and pharmacokinetics of T-2 toxin and related trichothecenes. Drug Metab Rev. 1993 25(3) 281 323. 

C22H32O8, Mr 424.49, light yellow oil. Mycotoxin of the tric(h)othecene group formed by various Fusa-rium species. It is also formed in the metabolism of T-2 toxin. In comparison to the latter, H. is about 3- to 10-times less toxic. Otherwise it exhibits the typical properties of the trichothecenes. LD50 (mouse i.p.) 9mg/kg. 

Some large scale and/or blocked fermentations with Trichothecium roseum or Fusarium spp. have yielded a number of metabolic products with structures closely related to the trichothecenes. These relatives, 49 in number (including 2 likely artefacts), an addition of six since 1995, are listed in Table 8 (structures Scheme 1), together with their sources. They consist mainly of... 

The Fusarium spp. metabolic products sambucinol (81) and its derivatives diacetylsambucinol (82) and 3-deoxysambucinol (80) can be regarded as ll-epi-12-epitrichothecenes but are more conveniently classified with the trichothecene relatives (Table 8), as is gramilaurone (98). These compounds are excluded from Tables 1-4 and the total of trichothecenes, as is the isotrichothecin 233) whose C-nmr spectrum is indistinguishable from that of trichothecin. 

The simple trichothecenes are products of Acremonium, Fusarium, Myrothecium, Stachybotrys and Trichoderma spp., and one species each of Cephalosporium, Cylindrocladium, Dendrostilbella, Gliocladium, Memnoniella, Microdocium, Spicellum and Trichothecium. Trichothecium roseum is, nevertheless, responsible for 12 metabolic products with... 

Hesketh AR (1992) Metabolic Studies on the Transformation of Trichodiene to Trichothecene Mycotoxins. Mycotoxin Res 8 52... 

Xu Y-C, Huang X, Cai Y-S (1982) Isolation and Structure of CBD2 - A New Trichothecene Toxin. Weishengwu Xuebao 22 35 Chem Abstr 96 196245 Freeman GG, Morrison RI (1948) Trichothecin An Antifungal Metabolic Product of Trichothecium roseum Link. Nature (Lond) 162 30... 

Tamm Ch, Breitenstein W (1980) The Biosynthesis of Trichothecene Mycotoxins. In Steyn PS (ed.) The Biosynthesis of Mycotoxins. A Study in Secondary Metabolism, p. 69. Academic Press, New York... 

Udell MN, Dewick PM (1989) Metabolic Conversions of Trichothecene Mycotoxins De-Esterification Reactions Using Cell-Free Extracts of Fusarium. Z Naturforsch 44C 660... 

Baldwin NCP, Bycroft BW, Dewick PM, Gilbert J (1986) Metabolic Conversions of Trichothecene Mycotoxins Biotransformation of 3-Acetyldeoxynivalenol into Fusarenone X. Z Naturforsch 41C 845... 

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