Effects of nomifensine and its metabolites on dihydropteridine reductase

Nomifensine and three of its metabolites were studied as potential inhibitors of dihydropteridine reductase. Purified enzyme preparations from human liver and the P2 fraction of rat striatal synaptosomes were used as enzyme sources. Nomifensine and its 3'-hydroxyl derivative inhibit this enzyme from both sources at 1.3 to 3.5 X 10(-4)M (150 values). 4'-Hydroxylated nomifensines, however, non-competitively inhibited this enzyme with Ki values of 2.8 to 4.4 X 10(-5)M. Dihydropteridine reductase regenerates tetrahydrobiopterin, the required cofactor for the hydroxylation of tyrosine and tryptophan, from quinonoid dihydrobiopterin. Inhibition of this enzyme could reduce the availability of the biopterin cofactor for the synthesis of dopamine and 5-hydroxytryptamine.