Peterson D A, Gerrard J M, Rao G H, White J G
Prostaglandins Med. 1979 Feb;2(2):97-108. doi: 10.1016/0161-4630(79)90044-2.
The molecular mechanism by which indomethacin exerts its inhibitory effects on the prostaglandin endoperoxide synthetase enzyme is unknown. In the present study we have explored the possibility that indomethacin might interact with Fe++ in the enzyme to produce its inhibitory effect. For this study we made use of the recent discovery that Fe++ alone can oxidize arachidonic acid, and the interaction of this fatty acid with the metal can be detected by following reduction of nitroblue tetrazolium (NBT) or by conversion of the Fe++ to Fe+++. Indomethacin markedly inhibited NBT reduction in the presence of arachidonic acid and Fe++ when the indomethacin had been preincubated with the Fe++. Indomethacin also inhibited the conversion of Fe++ to Fe+++ by arachidonic acid. Results obtained by varying the concentrations of indomethacin and arachidonic acid and measuring inhibition of the conversion of Fe++ to Fe+++ by the indomethacin are consistent with a one to one complex forming between indomethacin and Fe++. The complex between indomethacin and Fe++ separates on prolonged incubation of the complex with arachidonic acid. The nature of the binding is suggested by a molecular model. Our results suggest that indomethacin may act to inhibit the prostaglandin endoperoxide synthetase enzyme by complexing Fe++ in the enzyme. Ibuprofen and tolmetin, two other prostaglandin synthetase inhibitors, also inhibit the interaction of Fe++ with arachidonic acid suggesting this may be a general mechanism for this type of drug.
吲哚美辛对前列腺素内过氧化物合成酶发挥抑制作用的分子机制尚不清楚。在本研究中，我们探讨了吲哚美辛可能与该酶中的Fe++相互作用以产生抑制作用的可能性。在本研究中，我们利用了最近的一项发现，即单独的Fe++可以氧化花生四烯酸，并且这种脂肪酸与金属的相互作用可以通过跟踪硝基蓝四唑（NBT）的还原或通过将Fe++转化为Fe+++来检测。当吲哚美辛与Fe++预孵育后，在花生四烯酸和Fe++存在的情况下，吲哚美辛显著抑制NBT的还原。吲哚美辛还抑制花生四烯酸将Fe++转化为Fe+++。通过改变吲哚美辛和花生四烯酸的浓度并测量吲哚美辛对Fe++转化为Fe+++的抑制作用所获得的结果与吲哚美辛和Fe++之间形成1:1复合物一致。吲哚美辛与Fe++之间的复合物在与花生四烯酸长时间孵育后会分离。一个分子模型表明了结合的性质。我们的结果表明，吲哚美辛可能通过与该酶中的Fe++络合来抑制前列腺素内过氧化物合成酶。另外两种前列腺素合成酶抑制剂布洛芬和托美丁也抑制Fe++与花生四烯酸的相互作用，表明这可能是这类药物的普遍机制。
