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Title: TIME AND DOSE - RELATED CHANGES IN MOUSE SPHINGOLIPID METABOLISM FOLLOWING GAVAGE FUMONISIN B1 ADMINISTRATION

Author
item ENONGENE, E - FDA, WASHINGTON, DC
item BHANDARI, N - PHY/PHARM/VET MED, UGA
item Meredith, Filmore
item SHARMA, R - PHY/PHARM/VET MED, UGA
item Voss, Kenneth
item Riley, Ronald

Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 1/15/2001
Publication Date: 3/1/2001
Citation: N/A

Interpretive Summary:

Technical Abstract: Fumonisins (FB1), produced by the fungus Fusarium moniliforme, is a potent inhibitor of ceramide synthase (sphinganine [sphingosine] N-acyltransferase). High levels of free sphinganine in tissues and biological fluids are used as a biomarker for FB1 exposure. This study was design to determine the following: 1) the time course for sphingoid base elevation in the small intestine, liver, and kidney following a single oral administration of 25mg FB1/kg bw; and 2) the minimum threshold FB1 dose that would sustain the free sphingoid base concentration in the kidney (the tissue most sensitive to accumulation of free sphinganine) following a single gavage administration of FB1. The results indicate that there is a significant (p< 0.05) time-dependent increase in gut free sphinganine that peaks at 4-12 h and declines to near control level by 48h post dosing with complete restoration to control levels by 120h. A similar time-related pattern was seen in the liver, whereas in the kidney free sphinganine levels peaked at 6-12h but remained markedly elevated and only approached control levels at 96-120h. Daily administration of 0.03 mg FB1/kg bw for 5 days had no effect on the free sphingoid bases in the kidney, however, following an initial single gavage dose of 25 mg FB1/kg bw, daily doses of 0.03 mg FB1/kg bw significantly sustained kidney sphinganine levels when compared to kidney from mice treated with 25 mg/kg bw dose followed by daily gavage with saline. This findings suggests that a single dietary exposure to a high level of fumonisin followed by consumption of FB1 at low levels could sustain the free sphinganine elevation in kidney.