Regulation /Role--Ethanol Inducible Cytochrome P450 2e1

调节/作用--乙醇诱导细胞色素P450 2e1

基本信息

项目摘要

Alcohol drinking and certain pathophysiological conditions such as fasting and diabetes increase the levels of ethanol-inducible cytochrome P450 2E1 (CYP2E1) and other P450 enzymes in humans and animal models. It is now known that CYP2E1 can metabolize more than 70 substrates of different chemical structures. These CYP2E1 substrates include: ethanol, acetaldehyde, acetaminophen (APAP), 4-hydroxynonenal, carbon tetrachloride, long chain fatty acid including arachidonic acid, and nitrosamines. Increased CYP2E1 leads to elevated production of acetaldehyde, reactive oxygen species, free radical metabolites and lipid peroxides while reducing cellular anti-oxidants such as glutathione. Therefore, cells or tissues with increased CYP2E1 become more susceptible to damage or cell death, especially in the presence of an additional challenge. In the past, we have cloned the genes for human and rat CYP2E1 and demonstrated multiple regulatory mechanisms. Although other scientists already demonstrated cell damage (apoptosis and necrosis) by alcohol and acetaminophen using in vitro models, the molecular signaling mechanisms for their toxicities were not shown. During the last two or three years, we have been studying the role of elevated CYP2E1 in cell damage caused by alcohol and other CYP2E1 substrates and their mechanisms. Unlike other investigators who used CYP2E1-transfected HepG2 cells, we used C6 glioma cells since these cells contain CYP2E1, albeit in a small quantity, and undergo apoptosis upon exposure to CYP2E1 substrates. Therefore, we investigated our initial hypotheses that CYP2E1 substrates and their metabolites would activate the c-Jun N-terminal protein kinase (JNK) and p38 mitogen activated protein (MAP) kinase associated with cell death pathway while they would suppress the enzymes involved in the cell survival pathway. In addition, inhibition of CYP2E1 and JNK elevated during apoptosis effectively prevents cell death caused by CYP2E1 substrates. Our results showed that APAP caused time and dose-dependent apoptosis of C6 glioma cells. Activities of JNK and its immediate upstream kinase SEK-1 were rapidly increased 15 min after APAP exposure and this effect lasted up to 4 h. However, APAP did not activate the following enzymes: p38 MAP kinase, extracellular-signal regulated protein kinase (ERK), phosphatidylinositol 3-kinase, and Akt protein serine/threonine kinase. APAP-induced cell death was preceded by elevation of cytochrome c release and activation of caspase 3, a critical enzyme in executing apoptosis. We then demonstrated the critical role of the selective JNK activation in APAP-induced apoptosis by three key experiments: 1) transient transfection of the cDNA for JNK wild type or the dominant negative JNK KR mutant followed by cell death rate measurement; 2) differential effects of cytotoxic APAP and its non-toxic analog 3-hydroxyacetanilide on JNK activation and cell death rate; and 3) efficient blockade of JNK activation and cell death by pretreatment of C6 cells with the CYP2E1 inhibitor, YH439, which effectively suppressed the levels of CYP2E1 activity and protein content. These data indicate the critical role of CYP2E1-dependent metabolism and JNK activation during apoptosis. Our result of the selective JNK activation, therefore, is in contrast with other apoptotic stimuli such as hydrogen peroxide, UV and x-ray irradiations, and pro-inflammatory cytokines including tumor necrosis factor 1 alpha and interleukin 1 beta, all of which activate p38 MAP kinase along with the JNK in a coordinated fashion. Our in vitro results were also observed in in vivo models where APAP and carbon tetrachloride selectively and transiently increased the activities of JNK and SEK-1. Because of the critical role of selective activation of JNK-related pathway in cell damage caused by the three CYP2E1 substrates (APAP, 4-hydroxynonenal, and carbon tetrachloride), we are investigating whether other CYP2E1 substrates (including ethanol and arachidonic acid) cause cell damage by a similar mechanism.
在人类和动物模型中,饮酒和某些病理生理条件(如禁食和糖尿病)会增加乙醇诱导的细胞色素P450 2 E1(CYP 2 E1)和其他P450酶的水平。目前已知CYP 2 E1可以代谢70多种不同化学结构的底物。这些CYP 2 E1底物包括:乙醇、乙醛、对乙酰氨基酚(APAP)、4-羟基壬烯醛、四氯化碳、长链脂肪酸(包括花生四烯酸)和亚硝胺。CYP 2 E1增加导致乙醛、活性氧、自由基代谢物和脂质过氧化物的产生增加,同时减少细胞抗氧化剂如谷胱甘肽。因此,CYP 2 E1增加的细胞或组织变得更容易受到损伤或细胞死亡,特别是在存在额外挑战的情况下。在过去,我们已经克隆了人类和大鼠CYP 2 E1的基因,并证明了多种调控机制。虽然其他科学家已经使用体外模型证明了酒精和对乙酰氨基酚对细胞的损伤(凋亡和坏死),但其毒性的分子信号机制尚未显示。在过去的两三年里,我们一直在研究CYP 2 E1升高在酒精和其他CYP 2 E1底物引起的细胞损伤中的作用及其机制。与使用CYP 2 E1转染的HepG 2细胞的其他研究者不同,我们使用C6胶质瘤细胞,因为这些细胞含有CYP 2 E1,尽管数量很少,并且在暴露于CYP 2 E1底物时发生凋亡。因此,我们研究了我们最初的假设,即CYP 2 E1底物及其代谢产物将激活与细胞死亡途径相关的c-Jun N-末端蛋白激酶(JNK)和p38丝裂原活化蛋白(MAP)激酶,而它们将抑制参与细胞存活途径的酶。此外,抑制细胞凋亡过程中升高的CYP 2 E1和JNK可有效防止CYP 2 E1底物引起的细胞死亡。结果表明APAP诱导C6胶质瘤细胞凋亡具有时间和剂量依赖性。APAP暴露后15 min,JNK及其直接上游激酶SEK-1活性迅速升高,并持续4 h。然而,APAP不激活以下酶:p38 MAP激酶,细胞外信号调节蛋白激酶(ERK),磷脂酰肌醇3-激酶,Akt蛋白丝氨酸/苏氨酸激酶。APAP诱导的细胞死亡之前,细胞色素c的释放和激活caspase 3,在执行凋亡的关键酶的升高。然后我们通过三个关键实验证明了选择性JNK激活在APAP诱导的细胞凋亡中的关键作用:1)瞬时转染JNK野生型或显性阴性JNK KR突变体的cDNA,随后测量细胞死亡率; 2)细胞毒性APAP及其无毒类似物3-羟基乙酰苯胺对JNK激活和细胞死亡率的差异影响; CYP 2 E1抑制剂YH 439预处理C6细胞后,能有效阻断JNK的激活和细胞死亡,抑制细胞内CYP 2 E1的活性和蛋白质含量。这些数据表明细胞凋亡过程中CYP 2 E1依赖性代谢和JNK激活的关键作用。因此,我们的选择性JNK激活的结果与其他凋亡刺激如过氧化氢、UV和X射线照射以及促炎细胞因子包括肿瘤坏死因子1 α和白细胞介素1 β形成对比,所有这些都以协调的方式激活p38 MAP激酶沿着JNK。我们的体外结果也在体内模型中观察到,其中APAP和四氯化碳选择性地和瞬时地增加JNK和SEK-1的活性。由于JNK相关通路的选择性激活在由三种CYP 2 E1底物(APAP、4-羟基壬烯醛和四氯化碳)引起的细胞损伤中的关键作用,我们正在研究其他CYP 2 E1底物(包括乙醇和花生四烯酸)是否通过类似的机制引起细胞损伤。

项目成果

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BYOUNG-JOON SONG其他文献

BYOUNG-JOON SONG的其他文献

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{{ truncateString('BYOUNG-JOON SONG', 18)}}的其他基金

Function Of The Mitochondrial Aldehyde Dehydrogenase 2
线粒体醛脱氢酶 2 的功能
  • 批准号:
    6530276
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Alcohol Metabolism, Functional Consequences and Apoptosis Signaling Mechanism
酒精代谢、功能后果和细胞凋亡信号机制
  • 批准号:
    8148171
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Functional Role Of The Mitochondrial Aldehyde Dehydrogen
线粒体醛脱氢的功能作用
  • 批准号:
    6676960
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Alcohol Metabolism, Functional Consequences and Apoptosis Signaling Mechanism
酒精代谢、功能后果和细胞凋亡信号机制
  • 批准号:
    9568233
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Alcohol Metabolism, Functional Consequences and Apoptosis Signaling Mechanism
酒精代谢、功能后果和细胞凋亡信号机制
  • 批准号:
    10267509
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Alcohol Metabolism, Functional Consequence And Signaling
酒精代谢、功能后果和信号传导
  • 批准号:
    6982862
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Alcohol Metabolism, Functional Consequences and Apoptosis Signaling Mechanism
酒精代谢、功能后果和细胞凋亡信号机制
  • 批准号:
    8941370
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
REGULATION AND BIOLOGICAL ROLE OF ETHANOL INDUCIBLE CYTOCHROME P450 2E1 (CYP2E1)
乙醇诱导细胞色素 P450 2E1 (CYP2E1) 的调节和生物学作用
  • 批准号:
    6288632
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
ROLE OF ALDH2--TRANSGENIC MICE CARRYING ASIAN ALDH2-2 VARIANT ALLELE
ALDH2 的作用——携带亚洲 ALDH2-2 变异等位基因的转基因小鼠
  • 批准号:
    6431367
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Alcohol Metabolism, Functional Consequence And Signaling Mechanism
酒精代谢、功能后果和信号机制
  • 批准号:
    7732090
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:

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Jun Kinase Signaling and Apoptosis in Ischemia Stroke
缺血性中风中的 Jun 激酶信号转导和细胞凋亡
  • 批准号:
    6846304
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    6609989
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JUN Kinase Signaling in the Lung
肺部的 JUN 激酶信号传导
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    7092061
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JUN Kinase Signaling in the Lung
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Jun Kinase Signaling and Apoptosis in Ischemia Stroke
缺血性中风中的 Jun 激酶信号转导和细胞凋亡
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    6699667
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肺部的 JUN 激酶信号传导
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    6901828
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JUN Kinase Signaling in the Lung
肺部的 JUN 激酶信号传导
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    6787277
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ANGIOTENSIN II STIMULATED NEURONAL FOS AND JUN KINASE
血管紧张素 II 刺激神经元 FOS 和 Jun 激酶
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    6528477
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ANGIOTENSIN II STIMULATED NEURONAL FOS AND JUN KINASE
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    2001
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