2,4-DIAMINO-6-HYDROXYPYRIMIDINE, AN INHIBITOR OF TETRAHYDROBIOPTERIN SYNTHESIS, DOWN-REGULATES THE EXPRESSION OF INOS PROTEIN AND MESSENGER-RNA IN PRIMARY MURINE MACROPHAGES

2,4-diamino-6-hydroxy-pyrimidine (DAHP), an inhibitor of GTP cyclohydr olase I, blocks the synthesis of tetrahydrobiopterin (BH4), which is a known cofactor of inducible nitric oxide synthase (iNOS). Previously, DAHP was shown to suppress the production of nitric oxide by cytokine -activated fibroblasts, smooth muscle cells or endothelial cells which could be attributed to its function as a cofactor antagonist. Here, w e demonstrate that in interferon-gamma-activated murine peritoneal mac rophages DAHP suppresses the expression of iNOS mRNA and protein in a BH4-independent manner and, thus, acts by a novel mechanism.