Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor
Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor
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DOI：
10.1016/s0891-5849(02)01014-6
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发表时间：
2002-11-01
影响因子：
7.4
通讯作者：
Shertzer, HG
中科院分区：
文献类型：
--
作者：
Senft, AP;Dalton, TP;Shertzer, HG
2，3，7，8-四氯二苯并-对-二恶英（dioxin; TCDD）是一种普遍存在的环境污染物，可引起肝和肝外氧化应激。我们以前已经表明，二恶英增加线粒体呼吸依赖性活性氧的产生。在本研究中，我们研究了线粒体活性氧的产生对芳香烃受体（AHR），细胞色素P450 1A 1（CYP 1A 1），细胞色素P450 1A 2（CYP 1A 2），蛋白质被认为是重要的二恶英诱导的肝毒性的依赖。同源Ahr（-/-）、Cyp 1a 1（-/-）和Cyp 1a 2（-/-）基因敲除小鼠，以及C57 BL/6 J近交系小鼠作为其Ahr/Cyp 1a 1/Cyp 1a 2（+/+）野生型（wt）对应物，连续3天腹腔注射二恶英（15 μ g/kg体重）或玉米油溶剂。第一次治疗后一周检查了肝脏线粒体。载体处理的Ahr（-/-）小鼠中的线粒体H2 O2产生水平是载体处理的wt小鼠中发现的五分之一。而二恶英导致琥珀酸刺激的线粒体H，O2生产的野生型，Cyp 1a 1（-/-），Cyp 1a 2（-/-）小鼠，这种增加并没有发生与Ahr（-/-）敲除。Ahr（-/-）小鼠中H2 O2产生的缺乏不是由于低水平的Mn 2 +-超氧化物歧化酶（SOD 2）所示的Western免疫印迹分析，也不是由于高水平的线粒体谷胱甘肽过氧化物酶（GPX 1）活性。戴奥辛使野生型小鼠的线粒体顺乌头酸酶（一种被超氧化物灭活的酶）降低了44%，在Cvp 1a 2（-/-）小鼠中降低了26%，在Cyp 1a 1（-/-）小鼠中降低了24%;在Ahr（-/-）小鼠中没有观察到变化。戴奥辛处理增加了野生型、Cyp 1a 1（-/-）和Cyp 1a 2（-/-）小鼠的线粒体谷胱甘肽水平，但在Ahr（-/-）小鼠中没有。这些结果表明，组成和二恶英诱导的线粒体活性氧的产生与AHR的功能，这些影响是独立的CYP 1A 1或CYP 1A 2。(C)2002年爱思唯尔科学公司
2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin; TCDD) is a pervasive environmental contaminant that induces hepatic and extrahepatic oxidative stress. We have previously shown that dioxin increases mitochondrial respiration-dependent reactive oxygen production. In the present study we examined the dependence of mitochondrial reactive oxygen production on the aromatic hydrocarbon receptor (AHR), cytochrome P450 1A1 (CYP1A1), and cytochrome P450 1A2 (CYP1A2), proteins believed to be important in dioxin-induced liver toxicity. Congenic Ahr(-/-), Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice, and C57BL/6J inbred mice as their Ahr/Cyp1a1/Cyp1a2(+/+) wild-type (wt) counterparts, were injected intraperitoneally with dioxin (15 mug/kg body weight) or corn-oil vehicle on 3 consecutive days. Liver mitochondria were examined I week following the first treatment. The level of mitochondrial H2O2 production in vehicle-treated Ahr(-/-) mice was one fifth that found in vehicle-treated wt mice. Whereas dioxin caused a rise in succinate-stimulated mitochondrial H,02 production in the wt, Cyp1a1(-/-), and Cyp1a2(-/-) mice, this increase did not occur with the Ahr(-/-) knockout. The lack of H2O2 production in Ahr(-/-) mice was not due to low levels of Mn2+-superoxide dismutase (SOD2) as shown by Western immunoblot analysis, nor was it due to high levels of mitochondrial glutathione peroxidase (GPX1) activity. Dioxin decreased mitochondrial aconitase (an enzyme inactivated by superoxide) by 44% in wt mice, by 26% in Cvp1a2(-/-) mice, and by 24% in Cyp1a1(-/-) mice; no change was observed in Ahr(-/-) mice. Dioxin treatment increased mitochondrial glutathione levels in the wt, Cyp1a1(-/-), and Cyp1a2(-/-) mice, but not in Ahr(-/-) mice. These results suggest that both constitutive and dioxin-induced mitochondrial reactive oxygen production is associated with a function of the AHR, and these effects are independent of either CYP1A1 or CYP1A2. (C) 2002 Elsevier Science Inc.