Murine lymphocyte proliferation impaired by substituted neosolaniols and calonectrins--Fusarium metabolites associated with trichothecene biosynthesis.

The capacity of Fusarium secondary metabolites associated with trichothecene biosynthesis to inhibit murine spleen lymphocyte proliferation was evaluated and compared to that for well known trichothecenes. Activity of these compounds was not specific for B and T lymphocytes since they inhibited [3H]thymidine (TdR) incorporation in unstimulated, Con A- and LPS-stimulated lymphocytes to the same extent. Concentrations of 8-propionyl neosolaniol and 8-butyrylneosolaniol which inhibited [3H]Tdr uptake by 50% (ID50s) were 0.95 and 0.34 ng/ml, respectively. The ID50 for T-2 toxin was 0.26 ng/ml, indicating that there are minor alterations in 12,13-epoxytrichothecene toxicity resulting from the replacement of the isovaleryl moiety on C8 of the trichothecene skeleton with other bulky acyl groups. ID50 values for 4,15-diacetylnivalenol, fusarenon X, deoxynivalenol and 3-acetyldeoxynivalenol were 25, 38, 120 and 1800 ng/ml, respectively. Comparatively, ID50 values for 3,15-dideacetylcalonectrin, 15-deacetylcalonectrin, and 7,8-dihydroxycalonectrin were 390, 2700 and 2400 ng/ml, respectively, indicating that the modified calonectrins had equivalent or less toxicity. Lymphotoxicity of trichothecenes thus decreased upon substitution of acyl groups at the C8 with keto or hydroxy moieties and was also dependent on the nature of substitutions at the C3, C4 and C15 positions. Sambucinol and the trichothecene precursor trichodiene, metabolites which do not contain a 12,13-epoxide, did not inhibit lymphocyte proliferation. The results suggest the need for further assessment of occurrence and in vivo toxicity of Fusarium metabolites, particularly the substituted neosolaniols and calonectrins.