Evidence for cytochrome P-450 as a source of catalytic iron in myoglobinuric acute renal failure
Evidence for cytochrome P-450 as a source of catalytic iron in myoglobinuric acute renal failure
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DOI：
10.1038/ki.1996.53
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发表时间：
1996-02-01
影响因子：
19.6
通讯作者：
Shah, SV
中科院分区：
文献类型：
--
作者：
Baliga, R;Zhang, ZW;Shah, SV
铁在多种组织损伤模型中起重要作用，包括肌红蛋白尿急性肾功能衰竭。在这个模型中，受伤肌肉释放的肌红蛋白通常被认为是铁的来源。在本研究中，我们测量了肾脏中博莱霉素可检测的铁（能够催化自由基反应的铁），并检测了细胞色素P-450在甘油诱导的肌红蛋白尿急性肾功能衰竭模型中作为催化铁来源的作用。大鼠在夜间断水后ig 50%甘油（8ml /kg）， 24小时后处死。甘油处理的大鼠肾脏中博来霉素可检测的铁含量有显著的特异性增加，同时细胞色素P-450含量显著降低。然后我们检查了两种不同的细胞色素P-450抑制剂，西咪替丁（雷尼替丁为对照）和胡椒酰丁醇的效果。西咪替丁，而不是雷尼替丁，显著阻止甘油处理大鼠肾脏中博来霉素可检测铁的增加。细胞色素P-450含量的损失被西咪替丁和胡椒酰丁醇这两种抑制剂阻断，但雷尼替丁没有。这两种细胞色素P-450抑制剂对甘油诱导的急性肾功能衰竭都具有功能性（通过BUN和肌酐测量）和组织学保护作用。因此，我们的数据表明甘油处理的大鼠肾脏中博莱霉素可检测到的铁显著增加。我们的数据还表明，细胞色素P-450抑制剂对甘油诱导的急性肾功能衰竭提供保护，细胞色素P-450可能是急性肾功能衰竭模型中这种铁的重要来源。
Iron has been implicated to play an important role in several models of tissue injury, including myoglobinuric acute renal failure. In this model, myoglobin released from the injured muscle is generally accepted as a source of iron. In the present study we measured the bleomycin-detectable iron (iron capable of catalyzing free radical reactions) in the kidneys and examined the role of cytochrome P-450 as a source of catalytic iron in glycerol-induced model of myoglobinuric acute renal failure. Rats were injected with 50% glycerol (8 ml/kg) i.m. after overnight water deprivation and sacrificed 24 hours later. There was a marked and a specific increase in the bleomycin-detectable iron content accompanied by a marked decrease in the cytochrome P-450 content in the kidneys of glycerol treated rats. We then examined the effects of two different cytochrome P-450 inhibitors, cimetidine (with ranitidine as a control) and piperonyl butoxide. Cimetidine, but not ranitidine, significantly prevented the increase of bleomycin-detectable iron in the kidneys of glycerol-treated rats. The loss of cytochrome P-450 content was substantially blocked by both inhibitors, cimetidine and piperonyl butoxide, but not by ranitidine. Both the inhibitors of cytochrome P-450 provided functional (as measured by BUN and creatinine) and histological protection against glycerol-induced acute renal failure. Our data thus demonstrate a marked increase in bleomycin-detectable iron in the kidneys of glycerol-treated rats. Our data also indicate that inhibitors of cytochrome P-450 provide protection against glycerol-induced acute renal failure and that cytochrome P-450 may be a significant source of this iron in this model of acute renal failure.