In vitro toxicology of fumonisins and the mechanistic implications.
The effects of fumonisins B1(FB1), B2(FB2), and the backbone of fumonisin B1 remaining after hydrolysis of the tricarballylic groups with base (HFB1) on sphingolipid biosynthesis were studied in both primary rat hepatocytes and pig kidney epithelial cells (LLC-PK1). Fumonisins were potent inhibitors of sphingolipid biosynthesis in hepatocytes (IC50 of FB1 = 0.1 microM), but overt toxicity was not observed. In renal cells, fumonisins also inhibited sphingosine biosynthesis (IC50 for FB1 = 35 microM), and caused decreased cell proliferation as well. Higher doses (greater than or equal to 70 microM) killed renal cells after exposure for 3 days. The inhibition of de novo sphingolipid biosynthesis was specific, and appeared to be at the site of ceramide synthase, which catalyzes the formation of dihydroceramide or ceramide by the addition of the amide-linked fatty acid to sphinganine or sphingosine. These results may account for the ability of fumonisins to cause equine leucoencephalomalacia and to promote tumor formation.
Norred
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WP
Toxicology and Mycotoxin Research Unit, Richard B. Russell Agricultural Research Center, USDA/ARS, Athens, GA 30613.
Wang
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E
Yoo
H
H
Riley
R T
RT
Merrill
A H
AH
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects; D037341:Fumonisins; D007668:Kidney / Q000166:cytology / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D009183:Mycotoxins / Q000633:toxicity*; D014176:Protein Biosynthesis; D051381:Rats; D012694:Serine / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000378:metabolism; D013552:Swine
D002518:Ceramides; D037341:Fumonisins; D009183:Mycotoxins; D013107:Sphingolipids; C056934:fumonisin B2; C056933:fumonisin B1; D012694:Serine; D004247:DNA; D013110:Sphingosine