Free Radical Biochemistry, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.
Haematology Research, Department of Pathology and Biomedical Sciences, University of Otago Christchurch, New Zealand.
Free Radic Biol Med. 2020 May 20;152:142-151. doi: 10.1016/j.freeradbiomed.2020.03.002. Epub 2020 Mar 5.
Clinical measurement of neopterin has been extensively used as a marker of inflammation but the in vivo mechanism generating neopterin is poorly understood. Neopterin is described as the oxidation product of 7,8-dihydroneopterin, a potent antioxidant generated by monocyte/macrophages in response to interferon-γ. While peroxyl and hydroxyl scavenging generates dihydroxanthopterin, hypochlorite efficiently oxidises 7,8-dihydroneopterin into neopterin, but this reaction alone does not explain the high levels of neopterin seen in clinical data. Here, we examine whether superoxide scavenging by 7,8-dihydroneopterin generates neopterin. U937 cells incubated with oxLDL showed a time dependent increase superoxide and 7,8-dihydroneopterin oxidation to neopterin. Neopterin generation in oxLDL or phorbol ester treated U937 cells or human monocytes was inhibited by apocynin and PEG-SOD. Addition of the myeloperoxidase inhibitor 4-aminobenzoic acid hydrazide (ABAH) had no effect of the superoxide generation or neopterin formation. 7,8-Dihydroneopterin reacted with superoxide/hydroxy radical mixtures generated by X-ray radiolysis to give neopterin. Formation of neopterin by superoxide derived from the xanthine/xanthine oxidase system was inhibited by superoxide dismutase. Neopterin formation was inhibited by apocynin in phorbol ester treated human carotid plaque rings in tissue culture. These results indicate that 7,8-dihydroneopterin scavenges superoxide and is subsequently oxidised into neopterin in cellular and cell-free experimental systems.
新蝶呤的临床测量已被广泛用作炎症的标志物，但体内产生新蝶呤的机制尚未被很好地理解。新蝶呤被描述为 7,8-二氢新蝶呤的氧化产物，7,8-二氢新蝶呤是单核细胞/巨噬细胞在干扰素-γ的刺激下产生的一种强效抗氧化剂。虽然过氧自由基和羟自由基清除生成二羟黄嘌呤，次氯酸盐能有效地将 7,8-二氢新蝶呤氧化为新蝶呤，但仅这一反应并不能解释临床数据中观察到的高水平新蝶呤。在这里，我们研究了 7,8-二氢新蝶呤是否通过清除超氧阴离子来产生新蝶呤。用 oxLDL 孵育的 U937 细胞表现出超氧阴离子和 7,8-二氢新蝶呤氧化为新蝶呤的时间依赖性增加。oxLDL 或佛波酯处理的 U937 细胞或人单核细胞中的新蝶呤生成被 apocynin 和 PEG-SOD 抑制。髓过氧化物酶抑制剂 4-氨基苯甲酰肼 (ABAH) 的添加对超氧阴离子的产生或新蝶呤的形成没有影响。7,8-二氢新蝶呤与 X 射线辐射解产生的超氧阴离子/羟自由基混合物反应生成新蝶呤。黄嘌呤/黄嘌呤氧化酶系统衍生的超氧阴离子产生的新蝶呤形成被超氧化物歧化酶抑制。apocynin 在组织培养中的佛波酯处理的人颈动脉斑块环中抑制新蝶呤的形成。这些结果表明，7,8-二氢新蝶呤清除超氧阴离子，随后在细胞和无细胞实验系统中被氧化为新蝶呤。
