Metabolism of Trichothecene Mycotoxins

The substrate specificity of microsomal nonspecific carboxyesterase [EC 3.1.1.1] from rabbit and rat livers was studied in vitro by using seven (A)-type and six (B)-type 12,13-epoxytrichothecene mycotoxins. The C-4 acetyl residues of diacetoxyscirpenol, T-2 toxin, monoacetylnivalenol (fusarenon-X), and diacetylnivalenol were selectively hydrolyzed by the microsomal esterase to yield the corresponding C-4-deacetylated metabolites: monoacetoxyscirpenol, HT-2 toxin, nivalenol, and 15-acetylnivalenol, respectively. The C-3 acetyl group of monoacetyldeoxy-nivalenol and the C-8 acetyl group of tetraacetoxyscirpen were also deacetylated. Tri-acetoxyscirpen gave rise to two unidentified metabolites, which may include a C-4-deacetylated product. 8-Hydroxydiacetoxyscirpenol (neosolaniol), HT-2 toxin, acetyl-T-2 toxin and tetraacetylnivalenol were unaffected by this type of hydrolysis. It follows from these results that the C-4 acetyl residue is hydrolyzed by the microsomal carboxyesterase and substituents at C-3 and C-8 contribute to the selective enzymatic hydrolysis of the C-4 acetyl residue of trichothecenes. Kinetic analysis showed that rabbit microsomal esterase possessed a high affinity for (A)-type trichothecenes such as T-2 toxin and diacetoxyscirpenol, and that of rat microsomes possessed a high affinity for (B)-type trichothecenes such as monoacetylnivalenol (fusarenon-X). The significance of this specific deacetylation reaction is discussed in relation to the biological activity of the trichothecene derivatives as revealed by their inhibitory effect on protein synthesis in rabbit reticulocytes.