MECHANISM OF INHIBITION OF MYELOPEROXIDASE BY ANTIINFLAMMATORY DRUGS
MECHANISM OF INHIBITION OF MYELOPEROXIDASE BY ANTIINFLAMMATORY DRUGS
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DOI：
10.1016/0006-2952(91)90565-m
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发表时间：
1991-05-15
影响因子：
5.8
通讯作者：
WINTERBOURN, CC
中科院分区：
文献类型：
--
作者：
KETTLE, AJ;WINTERBOURN, CC
次氯酸（HOCl）是由人类嗜中性粒细胞产生的最强氧化剂，并且因此应该预期有助于由这些炎性细胞引起的损伤。 它由H2 O2和Cl-通过血红素酶髓过氧化物酶（MPO）产生。 我们使用H2 O2电极来评估各种抗炎药物抑制H2 O2转化为HOCl的能力。 氨苯砜、甲芬那酸、磺胺吡啶、奎纳克林、伯氨喹和氨基比林是有效的抑制剂，在约1 μ M或更低的浓度下，对H2 O2的初始损失速率的抑制率为50%。 光谱研究表明，抑制剂通过促进化合物II的形成，这是MPO的非活性氧化还原中间体。 抗坏血酸通过将化合物II还原回活性酶来逆转抑制。 通过测定相关酚类和苯胺类的抑制能力，确定了允许药物可逆地抑制MPO的特性。 随着芳环上的取代基吸电子量增加，抑制作用增加，直到达到最佳还原电位。 超过这个最佳值，它们的抑制能力下降。 最好的抑制剂是4-溴苯胺，其I50为45 nM。 最佳还原电位使抑制剂能够将MPO还原为化合物II，但阻止它们将化合物II还原回活性酶。 这种最佳还原潜力的开发将有助于靶向药物对抗HOCl依赖性组织损伤。
Hypochlorous acid (HOCl) is the most powerful oxidant produced by human neutrophils, and should therefore be expected to contribute to the damage caused by these inflammatory cells. It is produced from H2O2 and Cl- by the heme enzyme myeloperoxidase (MPO). We used a H2O2-electrode to assess the ability of a variety of anti-inflammatory drugs to inhibit conversion of H2O2 to HOCl. Dapsone, mefenamic acid, sulfapyridine, quinacrine, primaquine and aminopyrine were potent inhibitors, giving 50% inhibition of the initial rate of H2O2 loss at concentrations of about 1-mu-M or less. Phenylbutazone, piroxicam, salicylate, olsalazine and sulfasalazine were also effective inhibitors. Spectral investigations showed that the inhibitors acted by promoting the formation of compound II, which is an inactive redox intermediate of MPO. Ascorbate reversed inhibition by reducing compound II back to the active enzyme. The characteristic properties that allowed the drugs to inhibit MPO reversibly were ascertained by determining the inhibitory capacity of related phenols and anilines. Inhibition increased as substituents on the aromatic ring became more electron withdrawing, until an optimum reduction potential was reached. Beyond this optimum, their inhibitory capacity declined. The best inhibitor was 4-bromoaniline which had an I50 of 45 nM. An optimum reduction potential enables inhibitors to reduce MPO to compound II, but prevents them from reducing compound II back to the active enzyme. Exploitation of this optimum reduction potential will help in targeting drugs against HOCl-dependent tissue damage.