Dershwitz M, Novak R F
J Pharmacol Exp Ther. 1982 Aug;222(2):430-4.
The mechanism of nitrofurantoin-mediated depletion of red cell reduced glutathione (GSH) was investigated. Nitrofurantoin caused cellular depletion of GSH in vitro under aerobic and oxygen-depleted conditions, an effect which could be partially inhibited by coincubation with the hemeprotein ligand ethyl isocyanide, or completely prevented by coincubation with 2'-AMP, an inhibitor of NADPH-dependent reductase enzymes. Covalent binding of nitrofurantoin to red cell macromolecules appeared to be a minor process and was not substantially inhibited by either ethyl isocyanide or 2'-AMP. Covalent binding was only slightly greater under oxygen-depleted conditions. Nitrofurantoin increased the rate of superoxide formation in red cell lysate, an effect inhibited by ethyl isocyanide but not by 2'-AMP. These data suggest different mechanisms for nitrofurantoin-mediated depletion of GSH under aerobic and oxygen-depleted conditions. In the presence of oxygen, nitrofurantoin causes the release of superoxide from oxyhemoglobin. The superoxide thus formed may deplete GSH via several mechanisms. In the absence of oxygen, nitrofurantoin is reduced to reactive metabolites via reactions which appear to require the participation of both an NADPH-dependent flavoprotein and hemoglobin.
研究了呋喃妥因介导的红细胞还原型谷胱甘肽（GSH）消耗的机制。在需氧和缺氧条件下，呋喃妥因在体外可导致细胞内GSH消耗，与血红素蛋白配体乙基异氰化物共同孵育可部分抑制该效应，与NADPH依赖性还原酶的抑制剂2'-AMP共同孵育则可完全阻止该效应。呋喃妥因与红细胞大分子的共价结合似乎是一个次要过程，且未被乙基异氰化物或2'-AMP显著抑制。在缺氧条件下，共价结合仅略有增加。呋喃妥因可提高红细胞裂解液中超氧化物的生成速率，该效应可被乙基异氰化物抑制，但不能被2'-AMP抑制。这些数据表明，在需氧和缺氧条件下，呋喃妥因介导的GSH消耗机制不同。在有氧存在的情况下，呋喃妥因可导致氧合血红蛋白释放超氧化物。如此形成的超氧化物可能通过多种机制消耗GSH。在无氧条件下，呋喃妥因通过似乎需要NADPH依赖性黄素蛋白和血红蛋白共同参与的反应被还原为活性代谢产物。
