Inhibition of serine palmitoyltransferase activity in rabbit aorta by L-cycloserine.
Serine palmitoyltransferase (EC 2.3.1.50) initiates the biosynthesis of sphingolipids. Its activity is induced in the aortas of rabbits fed a Purina lab chow supplemented with 2% cholesterol (Williams, R. D., D. S. Sgoutas, and G. S. Zaatari. 1986. J. Lipid Res. 27: 763-770). Induction occurs during atherogenesis in parallel with increased arterial sphingomyelin concentrations. In this study, L-cycloserine was shown to be a potent inhibitor of serine palmitoyltransferase in aortas from New Zealand White rabbits. Activity was reduced in vitro by 50% using 5 microM L-cycloserine with 50 micrograms of microsomal protein. To assess in vivo inhibition, L-cycloserine was administered by intraperitoneal injection to rabbits maintained on either a standard Purina laboratory chow or one supplemented with 2% cholesterol. Serine palmitoyltransferase activity was inhibited by 76% in the aortas of rabbits on the standard chow 4 hr after a single 25 mg/kg body weight dose and 52% after a 10 mg/kg dose. Activity was reduced by 36% in animals on the standard chow and by 37% in the cholesterol-fed group after 1 week of daily doses. These experiments demonstrate that L-cycloserine inhibits serine palmitoyltransferase in aorta, and thus may be used to reduce sphingomyelin concentrations during experimental atherogenesis.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
R D
RD
Williams
D S
DS
Sgoutas
G S
GS
Zaatari
R A
RA
Santoianni
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology*; D003523:Cycloserine / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D011817:Rabbits; D051102:Serine C-Palmitoyltransferase; D013107:Sphingolipids / Q000378:metabolism
D013107:Sphingolipids; D003523:Cycloserine; D000217:Acyltransferases; D051102:Serine C-Palmitoyltransferase