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Journal of Lipid Research, Vol. 44, 1772-1779, September 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Metabolism of the unnatural anticancer lipid safingol, L-threo-dihydrosphingosine, in cultured cells

Mihaela Dragusin, Cristian Gurgui¹, Günter Schwarzmann, Joerg Hoernschemeyer and Gerhild van Echten-Deckert²

Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany

² To whom correspondence should be addressed. e-mail: g.echten.deckert{at}uni-bonn.de

We studied the metabolism of radioactively labeled safingol (L-threo-dihydrosphingosine) in primary cultured neurons, B104 neuroblastoma cells, and Swiss 3T3 fibroblasts, and compared it to that of its natural stereoisomer D-erythro-dihydrosphingosine. Both sphingoid bases are used as biosynthetic precursors for complex sphingolipids, albeit to different rates. Whereas a considerable amount of the natural sphingoid base is also directed to the catabolic pathway (20–66%, cell type dependent), only a minor amount of the nonnatural safingol is subjected to catabolic cleavage, most of it being N-acylated to the respective stereochemical variant of dihydroceramide. Interestingly, N-acylation of safingol to L-threo-dihydroceramide is less sensitive to fumonisin B1 than the formation of the natural D-erythro-dihydroceramide. In addition, safingol-derived L-threo-dihydroceramide, unlike its physiologic counterpart, is not desaturated. Most of it either accumulates in the cells (up to 50%) or is used as a biosynthetic precursor of the respective dihydrosphingomyelin (up to 45%). About 5% is, however, glucosylated and channeled into the glycosphingolipid biosynthetic pathway.

Our results demonstrate that, despite its nonnatural stereochemistry, safingol is recognized and metabolized preferentially by enzymes of the sphingolipid biosynthetic pathway. Furthermore, our data suggest that the cytotoxic potential of safingol is reduced rather than enhanced via its metabolic conversion.

Abbreviations: FB1, fumonisin B1; GSL, glycosphingolipid; S1P, sphingosine 1-phosphate; SM, sphingomyelin

Supplementary key words primary cultured neurons • neuroblastoma cells B104 • Swiss 3T3 cells • L-threo-sphinganine • ceramide

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