STRUCTURE-ACTIVITY-RELATIONSHIPS OF FUMONISINS IN SHORT-TERM CARCINOGENESIS AND CYTOTOXICITY ASSAYS

A short-term rat liver cancer initiation/promotion model was used to monitor the cancer-initiating activity of the mycotoxins fumonisin B1 (FB1), fumonisin B2 (FB2) and fumonisin B3 (FB3) as well as the N-acetyl derivatives of FB1 and FB2, and their respective hydrolysis products the aminopolyols. The induction of resistant hepatocytes, which develop into hepatocyte nodules on selection by the 2-acetylaminofluorene-partial hepatectomy promoting treatment, was taken as the endpoint for cancer initiation. When fed at a level of 1000 mg/kg diet for 21 days, only the fumonisins B were found to initiate cancer. In addition, these mycotoxins caused a marked reduction in the rat body weight during the initiating treatment. Comparative cytotoxicity studies in primary rat hepatocytes indicated that FB2 exhibited the highest cytotoxic effect followed by FB3 and FB1. In general, the fumonisin B mycotoxins exhibited a low cytotoxic effect in hepatocyte cultures, and the concentrations of FB1 and FB2 that caused a 50% (CD50) release of the total lactate dehydrogenase (LDH) were in the order of 2000 and 1000 muM, respectively. The N-acetyl derivatives also exhibited a cytotoxic effect, but were not as cytotoxic as the parent molecules at high concentrations. The respective aminopolyols exhibited a higher cytotoxicity than did the parent compounds, while tricarballylic acid (TCA) exhibited no dose response effect despite the fact that it had a higher background cytotoxicity compared with the control. The apparent inability of the aminopolyols to act as cancer initiators could be related to a lack in absorption from the gut. An active role of the TCA moiety in the absorption of the fumonisins from the gut was proposed. The present study indicated that the intact molecule and the presence of a free amino group determine the cancer-initiating activity of the fumonisins, and need to be considered in the detoxification procedures of these compounds in foods and feeds.