N-fatty acylation of hydrolyzed fumonisin B1, but not of intact fumonisin B1, strongly enhances in vitro mammalian toxicity

Fumonisin B-1 (FB1) is the most abundant of a series of sphingosine-analog mycotoxins produced by Fusarium verticilloides, 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 HFB1 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.