Shimizu S, Ishii M, Momose K, Yamamoto T
Department of Pathophysiology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Int J Mol Med. 1998 Nov;2(5):533-40. doi: 10.3892/ijmm.2.5.533.
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.
本综述讨论了（6R）-5,6,7,8-四氢生物蝶呤（H4生物蝶呤）在一氧化氮合酶（NOS）功能中的作用，以及H4生物蝶呤对一氧化氮（NO）和/或活性氧诱导的细胞毒性的保护作用。尽管在正常情况下，NOS释放的NO可调节血管张力和免疫监视，但当辅助因子之一的H4生物蝶呤或底物L-精氨酸减少时，NOS似乎会产生超氧阴离子和过氧化氢，这表明在病理条件下，NOS可能是活性氧的来源之一。此外，在H4生物蝶呤和/或L-精氨酸浓度不足的情况下，NO和活性氧的同时释放可能具有高毒性，因为NO与超氧阴离子和过氧化氢反应会形成具有毒性的过氧亚硝酸盐、单线态氧和羟基自由基。细胞内H4生物蝶呤含量的增加可避免NOS功能障碍（产生活性氧而非NO），并保护细胞免受与NOS功能障碍相关的细胞损伤。此外，H4生物蝶呤对活性氧具有强大的清除活性，并能抑制其细胞毒性。H4生物蝶呤还可能降低NO诱导的细胞毒性。因此，H4生物蝶呤不仅是NOS功能的重要调节剂，也是一种细胞内抗氧化剂。已知NO和活性氧与许多病理状态的发生发展有关。H4生物蝶呤可能对治疗许多疾病有效，如缺血再灌注损伤、炎症和糖尿病。
