2,4-Diamino-6-hydroxypyrimidine, an inhibitor of tetrahydrobiopterin synthesis, downregulates the expression of iNOS protein and mRNA in primary murine macrophages.
2,4-diamino-6-hydroxy-pyrimidine (DAHP), an inhibitor of GTP cyclohydrolase 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, we demonstrate that in interferon-gamma-activated murine peritoneal macrophages DAHP suppresses the expression of iNOS mRNA and protein in a BH4-independent manner and, thus, acts by a novel mechanism.
Bogdan
C
C
Institute for Clinical Microbiology and Immunology, University of Erlangen, Germany.
Werner
E
E
Stenger
S
S
Wachter
H
H
Röllinghoff
M
M
Werner-Felmayer
G
G
D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D015153:Blotting, Western; D005260:Female; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects*; D007042:Hypoxanthines / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase; D012333:RNA, Messenger / Q000378:metabolism*
D007042:Hypoxanthines; D012333:RNA, Messenger; D001708:Biopterins; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006136:GTP Cyclohydrolase; C017202:2,4-diaminohypoxanthine; C003402:sapropterin