ROLE OF TETRAHYDROBIOPTERIN IN THE FUNCTION OF NITRIC-OXIDE SYNTHASE,AND ITS CYTOPROTECTIVE EFFECT (REVIEW)

This review discusses the role of (6R)-5,6,7,8-tetrahydrobiopterin (H- 4 biopterin) in the function of nitric oxide synthase (NOS), and the p rotective effect of H-4 biopterin against nitric oxide (NO)- and/or re active oxygen species-induced cytotoxicity. Although NOS releases NO, which regulates vascular tone and immune surveillance under normal con ditions, NOS seems to produce superoxide anion and hydrogen peroxide w hen H-4 biopterin, one of the cofactors, or L-arginine, a substrate, i s decreased, suggesting the possibility that NOS is a source of reacti ve oxygen species under pathological conditions. Moreover, simultaneou s release of NO and reactive oxygen species in the presence of subopti mal concentrations of H-4 biopterin and/or L-arginine may be highly to xic, since NO reacts with superoxide anion and hydrogen peroxide to fo rm peroxynitrite, singlet oxygen and the hydroxyl radical, which are t oxic. An increase in H-4 biopterin content in cells obviates NOS dysfu nction (production of reactive oxygen species instead of NO) and prote cts the cells against NOS dysfunction-related cell injury. Moreover, H -4 biopterin has a strong scavenging activity for reactive oxygen spec ies, and inhibits thier cytotoxicity. H-4 biopterin is also likely to reduce NO-induced cytotoxicity. Thus, H-4 biopterin is not only an imp ortant regulator of NOS function, but is also an intracellular antioxi dant. NO and,reactive oxygen species are known to be implicated in the development of many pathological states. It is possible that H-4 biop terin could be effective for treating many diseases, such as ischemia- reperfusion injury, inflammation and diabetes mellitus.