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

Mihaela Dragusin, Cristian Gurgui, Günter Schwarzmann, Joerg Hoernschemeyer, and Gerhild van Echten-Deckert

Department of Organic Chemistry and Biochemistry, Kekulé-Institut, Bonn 53121

Corresponding Author: 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 non-natural 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 of its non-natural 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.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

M. Zollinger, C. Sayer, R. Dannecker, W. Schuler, and R. Sedrani
The Macrolide Everolimus Forms an Unusual Metabolite in Animals and Humans: Identification of a Phosphocholine Ester
Drug Metab. Dispos., August 1, 2008; 36(8): 1457 - 1460.
[Abstract] [Full Text] [PDF]

S. Batra, C. P. Reynolds, and B. J. Maurer
Fenretinide Cytotoxicity for Ewing's Sarcoma and Primitive Neuroectodermal Tumor Cell Lines Is Decreased by Hypoxia and Synergistically Enhanced by Ceramide Modulators
Cancer Res., August 1, 2004; 64(15): 5415 - 5424.
[Abstract] [Full Text] [PDF]

All ASBMB Journals	Journal of Biological Chemistry
Molecular and Cellular Proteomics	ASBMB Today

				S. Batra, C. P. Reynolds, and B. J. Maurer Fenretinide Cytotoxicity for Ewing's Sarcoma and Primitive Neuroectodermal Tumor Cell Lines Is Decreased by Hypoxia and Synergistically Enhanced by Ceramide Modulators Cancer Res., August 1, 2004; 64(15): 5415 - 5424. [Abstract] [Full Text] [PDF]