GTP cyclohydrolase I is coinduced in hepatocytes stimulated to produce nitric oxide.

Abstract 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 α, interleukin-1 β, and interferon-γ. 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.