Departments of Radiation Oncology (R.J.G.C., C.S.R., E.L.H., A.A., R.B.M.), Pharmacology and Toxicology (C.S.R., G.R.R., H.I.A.), and Human and Molecular Genetics (C.G., X.-Y.W.), Virginia Commonwealth University, Richmond, Virginia.
J Pharmacol Exp Ther. 2013 Oct;347(1):117-25. doi: 10.1124/jpet.113.203828. Epub 2013 Aug 2.
The effects of modulating tetrahydrobiopterin (BH4) levels with a metabolic precursor, sepiapterin (SP), on dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)-induced colorectal cancer were studied. SP in the drinking water blocks DSS-induced colitis measured as decreased disease activity index (DAI), morphologic criteria, and recovery of Ca(2+)-induced contractility responses lost as a consequence of DSS treatment. SP reduces inflammatory responses measured as the decreased number of infiltrating inflammatory macrophages and neutrophils and decreased expression of proinflammatory cytokines interleukin 1β (IL-1β), IL-6, and IL-17A. High-performance liquid chromatography analyses of colonic BH4 and its oxidized derivative 7,8-dihydrobiopterin (BH2) are inconclusive although there was a trend for lower BH4:BH2 with DSS treatment that was reversed with SP. Reduction of colonic cGMP levels by DSS was reversed with SP by a mechanism sensitive to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a specific inhibitor of the NO-sensitive soluble guanylate cyclase (sGC). ODQ abrogates the protective effects of SP on colitis. This plus the finding that SP reduces DSS-enhanced protein Tyr nitration are consistent with DSS-induced uncoupling of NOS. The results agree with previous studies that demonstrated inactivation of sGC in DSS-treated animals as being important in recruitment of inflammatory cells and in altered cholinergic signaling and colon motility. SP also reduces the number of colon tumors in AOM/DSS-treated mice from 7 to 1 per unit colon length. Thus, pharmacologic modulation of BH4 with currently available drugs may provide a mechanism for alleviating some forms of colitis and potentially minimizing the potential for colorectal cancer in patients with colitis.
用代谢前体物——蝶酰三谷氨酸（SP）调节四氢生物蝶呤（BH4）水平对葡聚糖硫酸钠（DSS）诱导的结肠炎和氧化偶氮甲烷（AOM）诱导的结直肠癌的影响进行了研究。饮用水中的 SP 可阻止 DSS 诱导的结肠炎，其表现为疾病活动指数（DAI）下降、形态学标准改善，以及由于 DSS 处理而丧失的 Ca2+诱导收缩反应得到恢复。SP 减少了炎症反应，表现为浸润性炎症巨噬细胞和中性粒细胞数量减少，以及促炎细胞因子白细胞介素 1β（IL-1β）、IL-6 和 IL-17A 的表达减少。虽然 DSS 处理后 BH4：BH2 有下降趋势，但高效液相色谱分析结肠 BH4 及其氧化衍生物 7,8-二氢生物蝶呤（BH2）的结果并不明确，而 SP 则可逆转这种趋势。DSS 降低结肠 cGMP 水平的作用可通过 1H-[1,2,4]恶二唑[4,3-a]喹喔啉-1-酮（ODQ）逆转，ODQ 是一种对一氧化氮敏感的可溶性鸟苷酸环化酶（sGC）的特异性抑制剂。ODQ 可消除 SP 对结肠炎的保护作用。再加上 SP 可减少 DSS 增强的蛋白 Tyr 硝化的发现，这与 DSS 诱导的 NOS 解偶联一致。这些结果与先前的研究结果一致，即 DSS 处理的动物中 sGC 的失活对于炎症细胞的募集以及胆碱能信号和结肠运动的改变很重要。SP 还可将 AOM/DSS 处理的小鼠的结肠肿瘤数量从每单位结肠长度 7 个减少到 1 个。因此，用现有药物调节 BH4 的药理学方法可能为缓解某些形式的结肠炎并最大限度地降低结肠炎患者发生结直肠癌的潜在风险提供一种机制。
