N-Fatty Acylation of Hydrolyzed Fumonisin B₁, but Not of Intact Fumonisin B₁, Strongly Enhances In Vitro Mammalian Toxicity

Fumonisin B₁ (FB₁) is the most abundant of a series of sphingosine-analog mycotoxins produced by Fusarium verticillioides, the major fungal contaminant of stored corn (maize) world-wide. Fumonisins were originally isolated as environmental tumor promoters, and they remain a concern because they are frequent contaminants of corn-derived food products intended for direct human consumption. FB₁ inhibits ceramide synthase, which may account for its acute toxic effects, but understanding of its tumor promotion mechanism has been limited by the general lack of understanding in the field. There is no evidence for functional metabolism of fumonisins in mammals, but abiogenic conversions during food processing are a concern because some known conversion products retain biological activity, including hydrolyzed FB₁ (HFB₁). HFB₁, formed by alkaline removal of FB₁ side chains, is a frequent contaminant of lime-treated corn products such as tortillas and tortilla chips. Humpf et al. (J. Biol. Chem., 273, 19060, 1998) observed that HFB₁ not only inhibits ceramide synthase, but it is converted to a ceramide analog with about ten times the in vitro mammalian toxicity of intact FB₁. In the present study we have confirmed this observation by preparing a series of ceramide analogs of HFB ₁ with varying fatty acid chain lengths and degree of unsaturation. Optimal in vitro mammalian toxicity was observed with fatty acid chain lengths of 10-14 carbons. However, ceramide analogs of HFB₁ were not phytotoxic in vitro, and ceramide analogs of FB₁ were not toxic in either mammalian or plant in vitro bioassays.