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Title: ROLE OF PROLIFERATION IN THE TOXICITY OF FUMONISIN B1: ENHANCED HEPATOTOXICRESPONSE IN THE PARTIALLY HEPATECTOMIZED RAT

Author
item LI, WU - INTERDIS TOX PROG, UGA
item Riley, Ronald
item Voss, Kenneth
item Norred, William

Submitted to: Journal of Toxicology and Environmental Health
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/21/2000
Publication Date: 10/1/2000
Citation: N/A

Interpretive Summary: Fumonisins are made by a common mold that is found on corn. They are mycotoxins, meaning toxins made by fungi, can cause death of horses and pigs, and may cause cancer of the esophagus in parts of the world where people eat corn every day. We study fumonisins to learn how they cause toxicity, and what can be done to prevent it. We observed that fumonisins are more toxic if cells undergo division. Healthy liver cells removed from animals can be maintained in culture for only a few days because they do not actively divide. They are resistant to fumonisins. On the other hand, cells taken from cancerous liver divide in culture, and can be maintained indefinitely. These cells are much more sensitive to fumonisin toxicity. We theorized that liver in an intact animal, which undergoes very little cell division, would be more susceptible to fumonisin's toxicity if the cells could be made to divide. Surgically removing about one-third of the liver from a rat stimulates the remaining liver cells to start dividing, eventually replacing the lost liver in 4-5 days. Therefore, we subjected anesthetized rats to partial hepatectomy (the removal of part of the liver), and then gave the rat fumonisin. The response was compared to control rats that were anesthetized and given a "sham" operation in which the abdomen was opened, but no liver was removed. Signs of toxicity were greater and occurred more quickly in rats that had liver tissue removed. These results are important for helping our understanding of how these important toxins affect animals.

Technical Abstract: Fumonisins are produced by several Fusaria species that contaminate maize, and cause several fatal animal diseases. Fumonisin B1 (FB1), the predominant analog, is a tumor promoter and carcinogen in rodents. Fumonisins apparently cause toxicity by inhibiting ceramide synthase and disrupting sphingolipid metabolism. Although liver is a target organ of fumonisins in vivo, primary hepatocytes and liver slices in vitro are resistant to cytotoxicity when exposed to fumonisins. Hepatoma cell lines, on the other hand, are sensitive to the fumonisin toxicity. We therefore hypothesized that the cytotoxicity is dependent on rapid cell proliferation. Partially hepatectomized rats were dosed with FB1 to determine whether a greater toxic response occurs in proliferating liver. A dose-related increase in free sphingoid bases was caused by FB1 in sham operated rats, and the effect was enhanced by partial hepatectomy(PH). Serum cholesterol and enzymes were higher in PH-treated rats dosed with FB1 than those given PH without FB1 or sham operated, FB1-dosed rats. Multiple doses of FB1 after surgery elevated the number of apoptotic hepatocytes observed in both sham and PH-treated rats to about the same degree, suggesting that apoptosis is not associated with the enhanced cytotoxicity of FB1 in regenerating liver. The results show that proliferating cells are more sensitive to the toxic effects of fumonisins, possibly due to enhanced disruption of sphingolipid metabolism.