Opposing mechanisms of NADPH-cytochrome P450 oxidoreductase regulation by peroxisome proliferators
Opposing mechanisms of NADPH-cytochrome P450 oxidoreductase regulation by peroxisome proliferators
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DOI：
10.1016/s0006-2952(03)00004-2
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发表时间：
2003-03-15
影响因子：
5.8
通讯作者：
Corton, JC
中科院分区：
文献类型：
--
作者：
Fan, LQ;Coley, J;Corton, JC
过氧化物酶体增殖物（PPs）调节一系列啮齿动物P450基因，包括CYP 2B、CYP 2C和CYNA家族成员。我们假设，P450代谢系统的其他组件被改变暴露于PP的，包括NADPH-细胞色素P450氧化还原酶（P450 R），在P450依赖性反应中经常限速组件。在这项研究中，我们确定是否暴露于结构不同的PP改变P450 R mRNA和蛋白的表达。长期暴露于PP后，在雄性和雌性F-344大鼠肝脏和雄性大鼠肾脏中观察到P450 R mRNA水平增加。奇怪的是，在相同的处理条件下，雄性大鼠在暴露于PP Wy-14，643（[4-氯-6-（2，3-二甲氨基）嘧啶硫醇乙酸）（WY）或吉非罗齐（GEM）后，肝脏P450 R蛋白水平降低。P450 R蛋白的下调具有性别和组织特异性，因为PP暴露导致雌性大鼠肝脏[仅邻苯二甲酸二正丁酯（DBP）]和雄性大鼠肾脏（WY、GEM、DBP）中P450 R蛋白增加。在雄性野生型SV 129小鼠中，暴露于WY和邻苯二甲酸二乙基己酯（DEHP）后肝脏中的P450 R mRNA水平增加，暴露于DEHR后雄性肾脏中的P450 R mRNA水平增加。在小鼠肝脏或肾脏中未观察到PP对mRNA的诱导，因为小鼠肝脏或肾脏缺乏功能性过氧化物酶体增殖物激活受体α（PPARalpha），PPs在啮齿动物肝脏中作用的中心介质。在野生型雄性小鼠中，WY和DEHP处理后肝脏中的P450 R蛋白减少，WY处理后肾脏中的P450 R蛋白减少。在PPARalpha-null小鼠中未观察到P450 R蛋白的下调。这些研究表明，P450 R的表达在两个不同的水平，这两个是依赖于PPARalpha的PP的复杂的调节：上调转录水平在肝脏和肾脏和下调蛋白质水平在雄性大鼠和小鼠肝脏的一种新的转录后机制。(C)2003年爱思唯尔科学公司All rights reserved.
Peroxisome proliferators (PPs) regulate a battery of rodent P450 genes, including CYP2B, CYP2C, and CYNA family members. We hypothesized that other components of the P450-metabolizing system are altered by exposure to PP's, including NADPH-cytochrome P450 oxidoreductase (P450R), an often rate-limiting component in P450-dependent reactions. In this study, we determined whether exposure to structurally diverse PPs alters the expression of P450R mRNA and protein. Increases in P450R mRNA levels were observed in male and female F-344 rat livers and in male rat kidneys after chronic exposure of the animals to PPs. Paradoxically, under the same treatment conditions in male rats, liver P450R protein levels decreased after exposure to the PPs Wy-14,643 ([4-chloro-6-(2,3-xylidino)pyrimidynylthiol acetic acid) (WY) or gemfibrozil (GEM). The down-regulation of the P450R protein was sex- and tissue-specific in that exposure to PPs led to increases in P450R protein in female rat livers [di-n-butyl phthalate (DBP) only] and male rat kidneys (WY, GEM, DBP). In male wild-type SV129 mice, P450R mRNA levels increased in livers after exposure to WY and diethylhexyl phthalate (DEHP) and in male kidneys after exposure to DEHR Induction of mRNA by PPs was not observed in the liver or kidneys of mice, which lack a functional peroxisome proliferator-activated receptor alpha(PPARalpha), the central mediator of the effects of PPs in the rodent liver. In wild-type male mice, P450R protein was decreased in liver after WY and DEHP treatment and in kidneys after WY treatment. The down-regulation of the P450R protein was not observed in PPARalpha-null mice. These studies demonstrate the complex regulation of P450R expression by PPs at two different levels, both of which are dependent upon PPARalpha: up-regulation of transcript levels in liver and kidneys and down-regulation of protein levels in male rat and mouse liver by a novel posttranscriptional mechanism. (C) 2003 Elsevier Science Inc. All rights reserved.