Ishii M, Shimizu S, Momose K, Yamamoto T
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Pharmacol Toxicol. 1998 Jun;82(6):280-6. doi: 10.1111/j.1600-0773.1998.tb01574.x.
The purpose of this study was to examine the effect of tetrahydrobiopterin, a co-factor of nitric oxide synthase, on H2O2-induced endothelial cell injury. Pretreatment with sepiapterin, a precursor of tetrahydrobiopterin biosynthesis, increased tetrahydrobiopterin content of endothelial cells, and reduced H2O2-induced endothelial cell injury, which was measured by leakage of lactate dehydrogenase. Both the increase in tetrahydrobiopterin content and the protective effect of sepiapterin were prevented by co-pretreatment with N-acetylserotonin, an inhibitor of sepiapterin reductase. Although Ca2+ ionophore ionomycin-induced nitric oxide synthesis was increased by pretreatment with sepiapterin, the protective effect of sepiapterin was not affected by an inhibitor of nitric oxide synthesis. On the other hand, pretreatment with sepiapterin also reduced H2O2-induced rat foetal lung fibroblast cell injury via an increase in tetrahydrobiopterin content, despite rat foetal lung fibroblast cells lacking nitric oxide synthase. Moreover, increase in tetrahydrobiopterin strongly reduced H2O2-induced intracellular oxidative stress. These findings indicate that sepiapterin reduces H2O2-induced endothelial cell injury via an increase in tetrahydrobiopterin content. Although increase in endothelial tetrahydrobiopterin content stimulated nitric oxide production, the protective effect of tetrahydrobiopterin against H2O2-induced endothelial cell injury is unlikely to be related to the stimulation of nitric oxide release from nitric oxide synthase. The protective effect of tetrahydrobiopterin may involve reactive oxygen species-scavenging activity.
本研究的目的是检测一氧化氮合酶的辅助因子四氢生物蝶呤对过氧化氢诱导的内皮细胞损伤的影响。用四氢生物蝶呤生物合成的前体色氨酸进行预处理，可增加内皮细胞中四氢生物蝶呤的含量，并减少过氧化氢诱导的内皮细胞损伤，这种损伤通过乳酸脱氢酶的泄漏来测定。用色氨酸还原酶抑制剂N - 乙酰血清素共同预处理可阻止四氢生物蝶呤含量的增加和色氨酸的保护作用。虽然用色氨酸预处理可增加钙离子载体离子霉素诱导的一氧化氮合成，但色氨酸的保护作用不受一氧化氮合成抑制剂的影响。另一方面，尽管大鼠胎儿肺成纤维细胞缺乏一氧化氮合酶，但用色氨酸预处理也可通过增加四氢生物蝶呤含量来减少过氧化氢诱导的大鼠胎儿肺成纤维细胞损伤。此外，四氢生物蝶呤的增加可强烈减少过氧化氢诱导的细胞内氧化应激。这些发现表明，色氨酸通过增加四氢生物蝶呤含量来减少过氧化氢诱导的内皮细胞损伤。虽然内皮细胞中四氢生物蝶呤含量的增加刺激了一氧化氮的产生，但四氢生物蝶呤对过氧化氢诱导的内皮细胞损伤的保护作用不太可能与一氧化氮合酶释放一氧化氮的刺激有关。四氢生物蝶呤的保护作用可能涉及活性氧清除活性。
