Apoptosis-inducing natural products found in utero during murine pregnancy.
BACKGROUND
Hormones, lipids, vitamins and other biologically active small molecules can be removed from animal tissues by extraction with organic solvents. These compounds can have dramatic effects on cultured cells and the characterization of such compounds can lead to the discovery of new functions for known molecules, or even to the discovery of previously unknown compounds.


RESULTS
Organic-soluble compounds in 17.5-day-old mouse embryos were removed with tert-butylmethylether and found to induce apoptosis in T-antigen-transformed Jurkat T cells. These embryonic extracts were fractionated and their apoptosis-inducing components were identified as a mixture of polyunsaturated fatty acids, including arachidonic, docosatetraenoic and docosahexaenoic acids. Docosatetraenoic acid was the most potent apoptosis inducer with an effective dose (ED(50)) of 30 microM.


CONCLUSIONS
A family of polyunsaturated fatty acids is shown to be abundant in utero during pregnancy. Members of this family are able to induce cleavage of poly(ADP)ribose polymerase, and ultimately to induce apoptosis, in T-antigen-transformed Jurkat T cells. Free radical scavengers, including phenol and benzyl alcohol, block the apoptosis-inducing properties of these polyunsaturated fatty acids; this is consistent with a lipid peroxidation mechanism involving formation of hydroperoxy fatty acids.
Liberles
S D
SD
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
Schreiber
S L
SL
D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000737:chemistry* / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000302:isolation & purification / Q000502:physiology; D005260:Female; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D010920:Placenta / Q000737:chemistry* / Q000502:physiology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011247:Pregnancy
D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D016859:Lipoxygenase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D000469:Alkaline Phosphatase