Role of proliferation in the toxicity of fumonisin B1: enhanced hepatotoxic response in the partially hepatectomized rat.
Fumonisin mycotoxins are common contaminants of maize and cause several fatal animal diseases. Liver is a target organ of fumonisins in intact animals, but liver slices and primary hepatocytes, which do not proliferate in culture, are resistant to fumonisin exposure. Hepatoma cell lines, on the other hand, undergo cell division in culture and are sensitive to the toxic effects of fumonisins. It was therefore hypothesized that fumonisin cytotoxicity is dependent on cell proliferation. To test this hypothesis, the partially hepatectomized rat was used as a model to determine whether fumonisin produced greater toxicity in rapidly proliferating liver in vivo. Rats were dosed intraperitoneally with fumonisin B1 (FB1) 24 h after sham operation or partial hepatectomy (PH) and were killed 24 h later. The dose-related increase in free sphingoid bases (a biomarker of fumonisin exposure) was enhanced in the PH-treated rats. Serum cholesterol and enzymes were higher in PH-treated rats dosed with FB1 than in those given PH without FB1 or in sham-operated, FB1-dosed rats. Multiple daily doses of FB1 after surgery elevated the number of apoptotic hepatocytes in both sham-operated and PH-treated rats to about the same degree, suggesting that apoptosis is not associated with the enhanced cytotoxicity of FB1 in regenerating liver. Proliferating cells appear to be more sensitive to the toxic effects of fumonisins. This enhanced cytotoxicity may be related to the increased ability of fumonisins to disrupt sphingolipid metabolism in hepatectomized rats, but this is yet to be determined.
Li
W
W
University of Georgia, Athens, Georgia, USA.
Riley
R T
RT
Voss
K A
KA
Norred
W P
WP
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D037341:Fumonisins / Q000008:administration & dosage / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000601:surgery; D008297:Male; D009183:Mycotoxins / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors
D037341:Fumonisins; D009183:Mycotoxins; C056933:fumonisin B1; D013110:Sphingosine; C005682:safingol