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.
Williams
R D
RD
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
Sgoutas
D S
DS
Zaatari
G S
GS
Santoianni
R A
RA
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