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 (H4 biopterin) in the function of nitric oxide synthase (NOS), and the protective effect of H4 biopterin against nitric oxide (NO)- and/or reactive oxygen species-induced cytotoxicity. Although NOS releases NO, which regulates vascular tone and immune surveillance under normal conditions, NOS seems to produce superoxide anion and hydrogen peroxide when H4 biopterin, one of the cofactors, or L-arginine, a substrate, is decreased, suggesting the possibility that NOS is a source of reactive oxygen species under pathological conditions. Moreover, simultaneous release of NO and reactive oxygen species in the presence of suboptimal concentrations of H4 biopterin and/or L-arginine may be highly toxic, since NO reacts with superoxide anion and hydrogen peroxide to form peroxynitrite, singlet oxygen and the hydroxyl radical, which are toxic. An increase in H4 biopterin content in cells obviates NOS dysfunction (production of reactive oxygen species instead of NO) and protects the cells against NOS dysfunction-related cell injury. Moreover, H4 biopterin has a strong scavenging activity for reactive oxygen species, and inhibits thier cytotoxicity. H4 biopterin is also likely to reduce NO-induced cytotoxicity. Thus, H4 biopterin is not only an important regulator of NOS function, but is also an intracellular antioxidant. NO and reactive oxygen species are known to be implicated in the development of many pathological states. It is possible that H4 biopterin could be effective for treating many diseases, such as ischemia-reperfusion injury, inflammation and diabetes mellitus.
Shimizu
S
S
Department of Pathophysiology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Ishii
M
M
Momose
K
K
Yamamoto
T
T
D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D019610:Cytoprotection; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
D007527:Isoenzymes; D017382:Reactive Oxygen Species; D001708:Biopterins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C003402:sapropterin