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Title: Accumulation of 1-Deoxysphinganine in mammalian cells and tissues following fumonisin inhibition of ceramide synthase: a novel category of bioactive sphingoid bases and 1-Deoxydihydroceramides

Author
item Riley, Ronald
item Zitomer, Nicholas
item Mitchell, Trevor
item Voss, Kenneth
item BONDY, GENEVIEVE
item PRUETT, SARAH
item GARNIER, ETHEL
item LIEBESKIND, LANNY
item PARK, HYEJUNG
item WANG, ELAINE
item SULLARDS, CAMERON
item MERRILL, ALFRED

Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: 12/15/2008
Publication Date: 3/15/2009
Citation: Riley, R.T., Zitomer, N.C., Mitchell, T.R., Voss, K.A., Bondy, G.S., Pruett, S.T., Garnier, E., Liebeskind, L.S., Park, H., Wang, E., Sullards, C., Merrill, A.H. 2009. Accumulation of 1-Deoxysphinganine in mammalian cells and tissues following fumonisin inhibition of ceramide synthase: a novel category of bioactive sphingoid bases and 1-Deoxydihydroceramides. Toxicological Sciences 108:132.

Interpretive Summary: Abstract - no summary required

Technical Abstract: Fumonisin B1(FB) is a mycotoxin that inhibits ceramide synthases (CerS) and causes kidney and liver toxicity and other disease. CerS inhibition increases sphinganine (Sa), Sa 1-phosphate and a novel sphingoid base, 1-deoxysphinganine (1-deoxySa). The purpose of this study was to i) determine the cytotoxicity of 1-deoxySa, ii) verify that 1-deoxySa can become elevated in tissues of animals exposed to FB, and iii) determine if endogenous 1-deoxySa is N-acylated by CerS. In LLC-PK1 cells, Vero cells, and other cell lines, 1-deoxySa accumulated to high levels after treatment with FB. 1-DeoxySa was also detected in liver and kidney of P53N5 mice and increased in mice fed FB diets. 1-DeoxySa displayed a similar toxicity as Sa in dividing LLC-PK1 cells. FB alone and FB plus 10 µM sphinganine co-treatment caused a slight elevation in 1-deoxySa compared to the control, whereas cells treated with FB plus 10 µM 1-deoxySa showed a 25-fold elevation in 1-deoxySa compared to the FB-only treated cells and a 42-fold elevation compared to the cultures treated with only 10 µM 1-deoxySa. Conversely, in LLC-PK1 cells treated with 10 µM 1-deoxySa, the level of total N-acyl-1-deoxySa (i.e., 1-deoxydihydroceramides) went from 32.2 to 4,634 pmol/mg protein. Co-treatment with FB reduced the increase to 396 pmol/mg protein, indicating that the endogenous 1-deoxySa is acylated by CerS. 1-Deoxydihydroceramides were also easily detected in mouse liver. These findings implicate 1-deoxy sphingoid bases in diseases caused by FB, and they may play important roles in cell regulation.