Warfarin administration reduces synthesis of sulfatides and other sphingolipids in mouse brain.
The modulation of phosphosphingolipid synthesis by vitamin K depletion has been observed in the vitamin K-dependent microorganism, Bacteriodes levii. When cultured briefly without the vitamin, a reduction occurred in the activity of the first enzyme of the sphingolipid pathway, 3-ketodihydrosphingosine synthase. In this report, 16-day-old mice were treated with the vitamin K antagonist, warfarin. Brain microsomes from these animals showed a 19% reduction in synthase activity. Mice treated with warfarin for 2 weeks showed a major reduction in sulfatide level (42%), with a lesser degree or no reduction in levels of gangliosides and cerebrosides. In further experiments, mice were treated with warfarin for 2 weeks and a group was then injected with vitamin K1 (aquamephyton) for 3 days. Enzyme activity returned to a normal level within 2-3 days. Sulfatide levels had increased 33% in the vitamin K-injected group and ganglioside levels also increased, where levels of cerebrosides and sphingomyelin declined. Sulfatide synthesis determined by [35S] sulfate incorporation, showed a 52% increase in incorporation following administration of vitamin K for 3 days. These results suggest a role for vitamin K in the biosynthesis of sulfatides and other sphingolipids in brain. This putative role could be by post-translational protein modification analogous to the role of vitamin K in other systems.
Sundaram
K S
KS
CUNY Medical School, NY 10031.
Lev
M
M
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006028:Glycosphingolipids / Q000096:biosynthesis; D051379:Mice; D008813:Mice, Inbred ICR; D007652:Oxo-Acid-Lyases / Q000378:metabolism; D010743:Phospholipids / Q000096:biosynthesis; D013107:Sphingolipids / Q000096:biosynthesis*; D013433:Sulfoglycosphingolipids / Q000096:biosynthesis*; D014812:Vitamin K / Q000008:administration & dosage / Q000502:physiology; D014813:Vitamin K Deficiency / Q000378:metabolism; D014859:Warfarin / Q000008:administration & dosage*
D006028:Glycosphingolipids; D010743:Phospholipids; D013107:Sphingolipids; D013433:Sulfoglycosphingolipids; D014812:Vitamin K; D014859:Warfarin; C021473:3-ketodihydrosphingosine synthetase; D007652:Oxo-Acid-Lyases