Inhibition of Sphingolipid Synthesis by Cycloserine In Vitro and In Vivo

Abstract

D- and L-cycloserine were irreversible inhibitors of the 1st enzyme of the sphingolipid pathway, 3-ketodihydrosphingosine synthetase, in a study using bacterial and mouse brain microsomal enzymes. L-Cycloserine was 100 times more inhibitory than the D-isomer for the brain microsomal enzyme in vitro. In vivo, L-cycloserine caused a 70% inhibition of brain microsomal enzyme. Following 1 injection, enzyme activity recovered 80% of normal after 16 h. Daily dosages of L-cycloserine on a regimen of i.p. injection for 7 days caused a significant reduction in total brain ganglioside and cerebroside plus sulfatide levels.