RT Journal Article
SR Electronic
T1 Synthetic Phytoceramides Induce Apoptosis with Higher Potency than Ceramides
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1249
OP 1255
DO 10.1124/mol.59.5.1249
VO 59
IS 5
A1 Onyou Hwang
A1 Guncheol Kim
A1 Yeon Joo Jang
A1 Seong Who Kim
A1 Guiyong Choi
A1 Hyun Jin Choi
A1 Seon Young Jeon
A1 Don Gyu Lee
A1 Jae Dam Lee
YR 2001
UL http://molpharm.aspetjournals.org/content/59/5/1249.abstract
AB Ceramides are naturally occurring compounds recognized to mediate apoptosis. N-acylsphingosines, containing a double bond at carbons 4 and 5 of their sphingoid backbone, are thought to be the active form, because N-acylsphinganines with completely saturated sphingoid are inactive. In the present study, we synthesized a series of N-acyl-4d-ribo-phytosphingosines (phytoceramides) that contain a hydroxyl group at carbon 4 and investigated structure-cytotoxicity relationship of the presumed functional groups in ceramides. N-Acetylphytoceramide (PCer2) and N-hexanoylphytoceramide (PCer6) were found to be more cytotoxic than ceramides as determined by released lactate dehydrogenase activity and morphological criteria. This was not caused by intracellular conversion of phytoceramides to ceramides, because noN-hexanoylsphingosine was formed after incubation of cell lysate with PCer6. Among phytoceramides having acyl chains two to eight carbons long, the cytotoxicity was highest with five or six carbons. The carbonyl group of the amide bond did not seem to be critical, because substitution of the oxygen with sulfur did not influence the cytotoxicity. The phytoceramide-induced cell death was observed to be apoptotic in nature with the use of terminal deoxynucleotidyl transferase dUTP nick-end labeling and propidium iodide staining. Because phytoceramides can be readily synthesized from yeast sources, they may present a potential and economical alternative to ceramide in future studies and therapies.