GTP cyclohydrolase I is coinduced in hepatocytes stimulated to produce nitric oxide.
GTP cyclohydrolase I is the rate-controlling enzyme in the production of tetrahydrobiopterin (BH(4)), an essential cofactor for nitric oxide (NO) synthase. Here we show that GTP cyclohydrolase I mRNA was present in unstimulated hepatocytes and was up-regulated 2- to 3-fold concurrently with iNOS induction induced in vivo by LPS injection and in vitro by stimulation with LPS and inflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta, and interferon-gamma. Hepatocyte GTP cyclohydrolase I enzyme activity increased 2-fold in vivo after LPS. This coinduction of GTP cyclohydrolase I resulted in increased total intracellular biopterin which supported induced NO synthesis. The addition of a GTP cyclohydrolase I inhibitor to the stimulated hepatocytes decreased intracellular biopterin levels and resulted in a decrease in NO production. The results show that GTP cyclohydrolase I is up-regulated by certain acute inflammatory conditions. Further, the results indicate that biopterin is essential as a cofactor for induced NO synthase activity in hepatocytes.
Geller
D A
DA
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Di Silvio
M
M
Billiar
T R
TR
Hatakeyama
K
K
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology; D004790:Enzyme Induction; D006136:GTP Cyclohydrolase / Q000096:biosynthesis*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D001708:Biopterins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006136:GTP Cyclohydrolase; C003402:sapropterin