Dillon Carolyn T, Hambley Trevor W, Kennedy Brendan J, Lay Peter A, Zhou Qingdi, Davies Neal M, Biffin J Ray, Regtop Hubert L
Centre for Heavy Metals Research, School of Chemistry, University of Sydney, NSW, 2006, Australia.
Chem Res Toxicol. 2003 Jan;16(1):28-37. doi: 10.1021/tx020078o.
Gastrointestinal (GI) toxicity is one of the major problems associated with antiinflammatory drugs. The complexation of the powerful antiinflammatory drug (IndoH) by metal ions, as a means of reducing GI toxicity, has been studied. The in vitro superoxide dismutase (SOD) activity, in vivo antiinflammatory activity, and gastrointestinal ulcerogenic properties of IndoH, [Cu2(Indo)4(DMF)2], and [Zn2(Indo)4(DMA)2] are reported. No SOD activity was observed for IndoH or [Zn2(Indo)4(DMA)2], but [Cu2(Indo)4(DMF)2] inhibited the reduction of nitroblue tetrazolium (NBT) at an IC50 value of 0.23 microM. All three compounds exhibited antiinflammatory activity in male Sprague-Dawley rats at an equivalent Indo dose of 10 mg/kg following oral administration of the drugs in 2% CMC solution. The severity of the toxicity (macroscopic ulcerations) in the stomach following oral dosing with [Zn2(Indo)4(DMF)2] was not significantly lower than that induced by IndoH (P = 0.78). Gastric ulcerations induced by [Cu2(Indo)4(DMF)2] were significantly lower than those induced by IndoH or [Zn2(Indo)4(DMA)2] (P = 0.0012 and P = 0.0175, respectively) but significantly greater than the control (P = 0.0013). The intestinal ulcerations induced by [Cu2(Indo)4(DMF)2] or [Zn2(Indo)4(DMA)2] were approximately 15 times lower than those of IndoH. A further indicator of gastrointestinal toxicity, caecal haemoglobin, increased in the following order: control < [Cu2(Indo)4(DMF)2] < [Zn2(Indo)4(DMA)2] < IndoH.[Cu2(Indo)4(DMF)2] exhibited the most promising results of the Indo complexes assayed, in that it exhibited SOD activity and the lowest gastrointestinal damage while also exhibiting antiinflammatory activity that was comparable to that for IndoH. Low-temperature EPR analyses also showed that the formulation used for [Cu2(Indo)4(DMF)2] administration was crucial to the integrity of the complex.
胃肠道（GI）毒性是与抗炎药相关的主要问题之一。人们研究了通过金属离子与强效抗炎药（IndoH）络合，以此降低胃肠道毒性的方法。本文报道了IndoH、[Cu2(Indo)4(DMF)2]和[Zn2(Indo)4(DMA)2]的体外超氧化物歧化酶（SOD）活性、体内抗炎活性以及胃肠道致溃疡特性。IndoH或[Zn2(Indo)4(DMA)2]未观察到SOD活性，但[Cu2(Indo)4(DMF)2]抑制氮蓝四唑（NBT）还原的IC50值为0.23微摩尔。在雄性Sprague-Dawley大鼠中，以10毫克/千克的等效Indo剂量口服给予2%羧甲基纤维素（CMC）溶液中的药物后，所有三种化合物均表现出抗炎活性。口服[Zn2(Indo)4(DMF)2]后胃中毒性（肉眼可见溃疡）的严重程度并不显著低于IndoH诱导的毒性（P = 0.78）。[Cu2(Indo)4(DMF)2]诱导的胃溃疡明显低于IndoH或[Zn2(Indo)4(DMA)2]诱导的胃溃疡（分别为P = 0.0012和P = 0.0175），但显著高于对照组（P = 0.0013）。[Cu2(Indo)4(DMF)2]或[Zn2(Indo)4(DMA)2]诱导的肠道溃疡比IndoH诱导的肠道溃疡低约15倍。胃肠道毒性的另一个指标——盲肠血红蛋白，按以下顺序升高：对照组 < [Cu2(Indo)4(DMF)2] < [Zn2(Indo)4(DMA)2] < IndoH。在测定的Indo络合物中，[Cu2(Indo)4(DMF)2]表现出最有前景的结果，因为它具有SOD活性，胃肠道损伤最低，同时抗炎活性与IndoH相当。低温电子顺磁共振（EPR）分析还表明，用于给药[Cu2(Indo)4(DMF)2]的制剂对络合物的完整性至关重要。
