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Toxicological Sciences 67, 173-181 (2002)
Copyright © 2002 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETICS

Persistence and Reversibility of the Elevation in Free Sphingoid Bases Induced by Fumonisin Inhibition of Ceramide Synthase

E. N. Enongene*, R. P. Sharma{dagger}, N. Bhandari{dagger}, J. D. Miller{ddagger}, F. I. Meredith*, K. A. Voss* and R. T. Riley*,1

* Toxicology and Mycotoxin Research Unit, R. B. Russell Research Center, USDA/ARS, P.O. Box 5677, Athens, Georgia 30604-5677; {dagger} College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602; and {ddagger} Department of Chemistry, Carleton University, Ottawa, Ontario, Canada K1S 5B6

These studies determined (1) the time course for sphingoid base elevation in the small intestines, liver, and kidney of mice following a single 25 mg/kg body weight (bw) oral dose (high dose) of fumonisin B1 (FB1), (2) the minimum threshold dose of FB1 that would prolong the elevated sphingoid base concentration in kidney following the single high dose, and (3) the importance of the balance between the rate of sphingoid base biosynthesis and degradation in the persistence of sphingoid base accumulation. Following the high dose of FB1, there was an increase in sphinganine in intestinal cells and liver that peaked at 4 to 12 h and declined to near the control level by 48 h. In kidney, sphinganine peaked at 6–12 h but remained elevated until 72 h, approaching control levels at 96–120 h. Oral administration of 0.03 mg FB1/kg bw (low dose) for 5 days had no effect on the sphingoid bases in kidney. However, following an initial high dose, daily administration of the low dose prolonged the elevation in kidney sphinganine compared to mice receiving a single high dose. Thus, a single exposure to a high dose of FB1 followed by daily exposure at low levels will prolong the elevation of sphinganine in kidney. In cultured renal cells FB1 was rapidly eliminated, but elevated sphinganine was persistent. This persistence in renal cells was rapidly reversed in the presence of the serine palmitoyltransferase inhibitor (ISP-1), indicating that the persistence was due to differences in the rates of sphinganine biosynthesis and degradation. The in vivo persistence in kidney may be due to similar differences.

Key Words: fumonisin; fusarium verticillioides; sphingolipids; liver; kidney; gastrointestinal; ceramide synthase; serine palmitoyltransferase; ISP-1; LLC-PK1 cells.


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