Role of cytochrome P-450 as a source of catalytic iron in cisplatin-induced nephrotoxicity
Role of cytochrome P-450 as a source of catalytic iron in cisplatin-induced nephrotoxicity
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DOI：
10.1046/j.1523-1755.1998.00161.x
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发表时间：
1998-11-01
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
背景。铁在自由基介导的组织损伤中发挥作用，包括顺铂诱导的肾毒性。然而，铁（催化自由基反应）的来源尚不清楚。我们检查了细胞色素 P-450 作为催化铁源在体内和体外顺铂诱导的肾毒性中的作用。方法。通过腹腔注射顺铂（10mg/kg体重）在大鼠中产生顺铂诱导的急性肾衰竭。胡椒基丁醚是一种细胞色素 P-450 抑制剂，在注射顺铂之前腹腔内给药（400 mg/kg 体重，两次，间隔 48 小时）。评估了在不存在或存在胡椒基丁醚的情况下顺铂对贝霉素可检测铁、肾脏中细胞色素 P-450 含量以及肾功能和组织学变化的影响。在一项体外研究中，检查了细胞色素 P-450 抑制剂西咪替丁或胡椒基丁醚对顺铂诱导的细胞毒性和 LLC-PK1 细胞催化铁释放的影响。结果。在顺铂治疗的大鼠中，肾脏中的细胞色素 P-450 含量显着降低，同时肾脏中博来霉素可检测到的铁含量增加。胡椒基丁醚可防止顺铂诱导的细胞色素 P-450 损失以及肾脏中博莱霉素可检测铁的增加，并提供功能和组织学保护。西咪替丁和胡椒基丁醚均可阻止顺铂诱导的博莱霉素可检测铁的增加和 LLC-PK1 细胞中的细胞毒性。西咪替丁治疗不影响细胞对顺铂的摄取。结论。细胞色素 P-450 是一组血红素蛋白，可能是顺铂诱导的肾毒性中催化铁的重要来源。
Background. Iron plays a role in free radical-mediated tissue injury, including cisplatin-induced nephrotoxicity. However, the source of iron (catalyzing free radical reactions) is not known. We examined the role of cytochrome P-450 as a source of catalytic iron in cisplatin-induced nephrotoxicity both in vivo and in vitro.Methods. Cisplatin-induced acute renal failure was produced in rats by intraperitoneal injection of cisplatin (10 mg/kg body wt). Piperonyl butoxide, a cytochrome P-450 inhibitor, was administered intraperitoneally (400 mg/kg body wt twice at 48-hr intervals) prior to cisplatin injection. The effects of cisplatin in the absence or presence of piperonyl butoxide on the belomycin-detectable iron, cytochrome P-450 content in the kidney, and renal functional and histological changes were evaluated. In an in vitro study, the effect of cytochrome P-450 inhibitors, cimetidine or piperonyl butoxide, on cisplatin-induced cytotoxicity and catalytic iron release from LLC-PK1 cells was examined.Results. In cisplatin-treated rats, there was a marked decrease in the cytochrome P-450 content specifically in the kidney, accompanied by increased bleomycin-detectable iron content in the kidney. Piperonyl butoxide prevented cisplatin-induced loss of cytochrome P-450 as well as the increase of bleomycin-detectable iron in the kidney, along with both functional and histological protection. Both cimetidine and piperonyl butoxide prevented cisplatin-induced increase in bleomycin-detectable iron and cytotoxicity in LLC-PK1 cells. Treatment of cimetidine did not affect cellular uptake of cisplatin.Conclusion. Cytochrome P-450, a group of heme proteins, may serve as a significant source of catalytic iron in cisplatin-induced nephrotoxicity.