Dose-dependent fumonisin B1 hepatotoxicity and hepatocarcinogenicity, detoxification of fumonisin B1, and suppression by isoflavones of fumonisin B1-promoted hepatocarcinogenesis in rats
To determine threshold dose of fumonisin B1 (FB1) hepatotoxicity and hepatocarcinogenicity, rats were initiated with diethylnitrosamine (DEN) and were fed 12.5, 25 and 50 ppm FB1 for 4 weeks. Comparing with control rats, significant increases in plasma alanine aminotransferase activities (ALT) and plasma total cholesterol (TC) were found in animals fed 25 and 50 ppm FB1, and greater hepatic prostaglandin (PG) production in 50 ppm FB1 group. Placental glutathione S-transferase (PGST)- and gamma-glutamyltransferase (GGT)-positive altered hepatic foci (AHF) developed only in 25 and 50 ppm FB1 groups, and feeding 50 ppm FB1 significantly increased the percent areas of PGST- and GGT-positive AHF compared with feeding 25 ppm FB1. The short-term threshold of FB1 hepatotoxicity and hepatocarcinogenicity, therefore, was probably >12.5 ppm but <25 ppm;Fumonisin B1 was reacted with fructose for detoxification. Rats were initiated with DEN and were fed 50 ppm FB1 or 50 ppm FB1 reacted with fructose (FB1-fructose) for 4 weeks. In comparison with the rats fed FB1-fructose, the FB1-fed rats had significantly increased plasma ALT activity, plasma TC, and hepatic PG synthesis. Only in the FB1-fed rats occurred PGST- and GGT-positive AHF. Liver-associated natural killer (NK) cell activity was significantly decreased in the FB1-fed rats and increased in the group fed FB1-fructose. Therefore, reacting FB1 with fructose detoxified FB1 while stimulating the NK cell activity;To evaluate the proposed anticarcinogenic ability of the soy isoflavones genistein and daidzein, DEN-initiated rats were fed 1 mmol total isoflavones/kg diet with 12.5, 25 and 50 ppm FB1 for 4 weeks. Greater plasma TC concentration, ALT activity, hepatic PG production, and development of PGST- and GGT-positive AHF were found in the rats fed diets containing 50 ppm FB1 regardless of isoflavone content. Significantly increased plasma ALT activity, plasma TC, and development of PGST- and GGT- positive AHF were shown in the rats fed 25 ppm FB1. These stimulatory effects of 25 ppm FB1, however, were diminished by isoflavones. Therefore, isoflavones suppressed rat hepatocarcinogenesis promoted by FB1 only at an FB1 dose of 25 ppm and not when 50 ppm was fed.