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.