Trichothecenes: Structure-Toxic Activity Relationships

Abstract

Trichothecenes comprise a large family of structurally related toxins mainly produced by fungi belonging to the genus Fusarium. Among trichothecenes, type A and type B are of the most concern due to their broad and highly toxic nature. In order to address structure-activity relationships (SAR) of trichothecenes, relationships between structural features and biological effects of trichothecene mycotoxins in mammalian systems are summarized in this paper. The double bond between C-9-C-10 and the 12,13-epoxide ring are essential structural features for trichothecene toxicity. Removal of these groups results in a complete loss of toxicity. A hydroxyl group at C-3 enhances trichothecene toxicity, while this activity decreases gradually when C-3 is substituted with either hydrogen or an acetoxy group. The presence of a hydroxyl group at C-4 promotes slightly lower toxicity than an acetoxy group at the same position. The toxicity for type B trichothecenes decreases if the substituent at C-4 is changed from acetoxy to hydroxyl or hydrogen at C-4 position. The presence of hydroxyl and hydrogen groups on C-15 decreases the trichothecene toxicity in comparison with an acetoxy group attached to this carbon. Trichothecenes toxicity increases when a macrocyclic ring exists between the C-4 and C-15. At C-8 position, an oxygenated substitution at C-8 is essential for trichothecene toxicity, indicating a decrease in the toxicity if substituent change from isovaleryloxy through hydrogen to the hydroxyl group. The presence of a second epoxy ring at C-7-C-8 reduces the toxicity, whereas epoxidation at C-9-C-10 of some macrocyclic trichothecenes increases the activity. Conjugated trichothecenes could release their toxic precursors after hydrolysis in animals, and present an additional potential risk. The SAR study of trichothecenes should provide some crucial information for a better understanding of trichothecene chemical and biological properties in food contamination.

Effects of Trichothecene Production on the Plant Defense Response and Fungal Physiology: Overexpression of the Trichoderma arundinaceum tri4 Gene in T. harzianum

“…Research has expanded to examine the structure-function relationships of the various trichothecenes and their intermediates on plants and other fungi. Cytotoxicity of HA on human tumor cell lines (17) and the importance to cytotoxicity of the moiety of the C-4 side chain of trichothecenes (18) have been reported. Trichodermin, which carries an ester group in the C-4 side chain, is more toxic than trichodermol, which contains a hydroxyl group in that position (18).…”

“…Cytotoxicity of HA on human tumor cell lines (17) and the importance to cytotoxicity of the moiety of the C-4 side chain of trichothecenes (18) have been reported. Trichodermin, which carries an ester group in the C-4 side chain, is more toxic than trichodermol, which contains a hydroxyl group in that position (18). In recent years, the role of HA in the biocontrol activity of Trichoderma arundinaceum has been investigated.…”

Therapeutic effects of three trichothecenes in the silkworm infection assay with <i>Candida albicans </i>

“…Trichothecenes are generally known as mycotoxins that have toxic effects on eukaryotic cells by inhibiting protein, DNA or RNA synthesis to induce apoptosis (11,12). In the present study, the known trichothecenes 1 to 3 exhibited antifungal activities.…”

Identification and Cytotoxic Activities of Two New Trichothecenes and a New Cuparane-Type Sesquiterpenoid from the Cultures of the Mushroom Engleromyces goetzii

“…Trichothecenes are an important source of contamination in food and feed [11,12]. When contaminated food and feed are ingested, trichothecenes initiate a wide range of acute and chronic symptoms, including cardiovascular lesions, hypotension, anemia and lymphoid necrosis [13,14]. The effects of trichothecenes on eukaryotic cells include the inhibition of protein, DNA and RNA synthesis, inhibition of mitochondrial functions and cell division, and membrane effects [14,16].…”