|Voss, Kenneth - Ken|
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.