Reaction of fumonisin with glucose prevents promotion of hepatocarcinogenesis in female F344/N rats while maintaining normal hepatic sphinganine/sphingosine ratios.

The reaction of the primary amine of fumonisin B(1) (FB(1)) with glucose was hypothesized to detoxify this mycotoxin. Eighty 10-day-old female F344/N rats were injected intraperitoneally with diethylnitrosamine (DEN; 15 mg/kg of body weight). At 4 weeks of age, the weaned rats were randomly assigned to one of four treatment groups with 20 rats each. At 9 weeks of age, four rats from each treatment group were killed. At 12 weeks, another five rats from each group were killed. At 20 weeks of age, the remaining rats were killed. In comparison with the rats fed basal diet or FB(1)-glucose (containing 25 ppm of FB(1)), rats fed 8 ppm (residual amount of free FB(1) in the FB(1)-glucose mixture) or 25 ppm of FB(1) had greater alanine aminotransferase activity at 9 and 20 weeks of age (P < 0.001), greater endogenous hepatic prostaglandin E(2) production at 20 weeks of age (P < 0.05), and significantly lower plasma cholesterol at 20 weeks of age (P < 0.01). Placental glutathione S-transferase (PGST)-positive and gamma-glutamyltransferase (GGT)-positive altered hepatic foci (AHF) occurred only in rats fed 25 ppm of FB(1) at 20 weeks of age. Hepatic natural killer (NK) cell activities were similar among the four groups, but the percentage of total liver-associated mononuclear cells exhibiting the NKR-P1(bright) marker was significantly greater in rats fed FB(1)-glucose, FB(1) (8 ppm) and FB(1) (25 ppm) than in control rats at 9 weeks of age, and FB(1)-glucose-treated rats had significantly lower NKR-P1(bright) cells as a percentage of total liver-associated mononuclear cells than rats fed 25 ppm of FB(1) at 20 weeks of age (P < 0.05). PGST- or GGT-positive AHF were not detected in any treatment group at 9 or 12 weeks of age. At 20 weeks of age, half of the rats fed 25 ppm of FB(1) had PGST- and GGT-positive AHF. The sphinganine (Sa) concentration and the Sa/sphingosine (So) ratio were significantly greater in the rats fed 25 ppm of FB(1) diet as compared with the control groups at, respectively, 12 or 20 weeks of age. Therefore, modifying FB(1) with glucose seems to prevent FB(1)-induced hepatotoxicity and promotion of hepatocarcinogenesis. The Sa/So ratio was not the most sensitive biomarker of FB(1) toxicity.