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Title: SERINE PALMITOYLTRANSFERASE INHIBITION REVERSES ANTI-PROLIFERATIVE EFFECTS OF CERAMIDE SYNTHASE INHIBITION IN CULTURED RENAL CELLS AND SUPPRESSES FREE SPHINGOID BASE ACCUMULATION IN KIDNEY OF BALBC MICE

Author
item Riley, Ronald
item Voss, Kenneth
item Norred, William
item Bacon, Charles
item Meredith, Filmore
item SHARMA, RAGHUBIR - PHY-PHRM/VET MED, U GA

Submitted to: Environmental Toxicology and Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/2/1998
Publication Date: N/A
Citation: N/A

Interpretive Summary: Fumonisins are toxic chemicals produced by the mold Fusarium moniliforme and Fusarium proliferatum which are commonly found on corn. When animals eat corn-based feeds containing toxic amounts of fumonisin, there is a marked change in a group of fats (sphingolipids) which are very important to the normal function of cells. The enzyme that is affected by fumonisins is called ceramide synthase and when it is inhibited, there is a very large increase in a chemical called sphinganine. Many of the changes that occur in cell function are suspected to be caused by sphinganine. The increase in sphinganine also contributes to the animal diseases. One of these diseases is a brain disease in ponies and another is a lung disease in pigs. Also, fumonisins are toxic to the liver of all animals tested and the kidney is most. This study used pig kidney cells to show that when the large increase in sphinganine is prevented using a chemical called myriocin, the toxic effect of fumonisin on the cells was also prevented. Myriocin was also given to mice and the increase in sphinganine caused by fumonisin was reduced. The result suggests that myriocin might be useful to treat animals that consumed toxic amounts of fumonisins in corn based feeds.

Technical Abstract: This study determined the ability of the fungal serine palmitoyltransferase (SPT) inhibitor, myriocin, to prevent the anti-proliferative and cytotoxic effects of fumonisin B1 in cultured pig kidney epithelial cells, LLC-PK1. The potent and selective fungal SPT inhibitor (myriocin) was partially purified from liquid cultures of Isaria sinclairii by a combination of organic extraction and column chromatography. The various fractions were bioassayed for their ability to inhibit fumonisin-induced sphinganine accumulation in LLC-PK1 cells. The activity in partially purified material was compared to the activity of highly purified myriocin and the results expressed as myriocin equivalents. The IC50 and IC95 for inhibition of fumonisin-induced sphinganine accumulation were approximately 2 to 5 nM and 20 to 30 nM, respectively. The IC95 concentration of the fungal SPT inhibitor reversed the antiproliferative effects and prevented fumonisin-induced apoptosis after 48 hour exposure to 50 uM fumonisin B1. The SPT inhibitor was also effective at reducing free sphinganine in vivo. Free sphinganine concentration was reduced 60% in kidney of mice injected i.p. with SPT inhibitor plus fumonisin B1 when compared to fumonisin B1 alone. The ability of SPT inhibition to reduce fumonisin B1-induced sphsinganine accumulation in vivo may be useful in the development of therapeutic agents for treatment of animals suspected to have been exposed to toxic levels of fumonisin in feeds.