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

GTP cyclohydrolase I is the rate-controlling enzyme in the production of te trahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) syntha se. Here we show that GTP cyclohydrolase I mRNA was present in unstimulated hepatocytes and was up-regulated 2- to 3-fold concurrently with iNOS induc tion 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 incr eased 8-fold in vivo after LPS. This coinduction of GTP cyclohydrolase I re sulted in increased total intracellular biopterin which supported induced N O synthesis. The addition of a GTP cyclohydrolase I inhibitor to the stimul ated hepatocytes decreased intracellular biopterin levels and resulted in a decrease in NO production. The results show that GTP cyclohydrolase I is u p-regulated by certain acute inflammatory conditions. Further, the results indicate that biopterin is essential as a cofactor for induced NO synthase activity in hepatocytes. (C) 2000 Academic Press.