Regulation of CYP2E1 by ethanol and palmitic acid and CYP4A11 by clofibrate in primary cultures of human hepatocytes.
Regulation of CYP2E1 by ethanol and palmitic acid and CYP4A11 by clofibrate in primary cultures of human hepatocytes.
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DOI：
10.1093/toxsci/kfh126
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发表时间：
2004-06
期刊：
影响因子：
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通讯作者：
J. Raucy;J. Lasker;K. Ozaki;Veronica Zoleta
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文献类型：
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作者：
J. Raucy;J. Lasker;K. Ozaki;Veronica Zoleta
CYP 2 E1和CYP 4A 11是细胞色素P450酶，受生理条件（包括糖尿病和禁食）调节。此外，已报告异种化学品氯贝特可诱导啮齿动物CYP 2 E1和CYP 4A。这些发现表明了类似的监管模式。两种酶的共同点还在于代谢脂肪酸如月桂酸和花生四烯酸的能力。在这里，我们使用人肝细胞的原代培养物来确定某些异种化学物质是否可以调节CYP 2 E1和CYP 4A 11。乙醇显著（p < 0.05）增加了CYP 2 E1 mRNA的表达，为对照组的216 +/- 32%，但没有改变CYP 4A 11 mRNA的积累（对照组的145 +/- 22%）。相比之下，暴露于乙醇的肝细胞仅显示CYP 2 E1蛋白轻微升高（对照的122 +/- 13%），对CYP 4A 11蛋白的影响可忽略不计。氯贝特显著（p < 0.05）增强CYP 4A 11 mRNA和蛋白，分别为对照组的239 +/- 30%和154 +/- 10%，但不增加CYP 2 E1。由于啮齿动物CYP 4A据报道是由脂肪酸通过过氧化物酶体增殖物激活受体α（PPARalpha）和CYP 2 E1诱导高脂肪饮食，我们检查了中链脂肪酸，棕榈酸对CYP 2 E1 mRNA含量的影响。棕榈酸显著（p < 0.05）增加CYP 2 E1 mRNA至对照组的326 +/- 57%。总的来说，本文提供的结果确定了在转录水平上增强CYP 2 E1和CYP 4A 11的药物，并表明脂肪酸可能代表了这些P450酶的类似调节模式。在人肝细胞中乙醇对CYP 2 E1蛋白缺乏诱导，表明对于某些P450酶，分离的肝细胞可能不是预测体内反应的适当工具。
CYP2E1 and CYP4A11 are cytochrome P450 enzymes that are regulated by physiological conditions including diabetes and fasting. In addition, the xenochemical clofibrate has been reported to induce both rodent CYP2E1 and CYP4A. These findings suggest similar modes of regulation. Also in common to both enzymes is the ability to metabolize fatty acids such as laurate and arachidonic acid. Here, we used primary cultures of human hepatocytes to determine if certain xenochemicals could regulate CYP2E1 and CYP4A11. Ethanol significantly (p < 0.05) increased expression of CYP2E1 mRNA by 216 +/- 32% of control, but did not alter CYP4A11 mRNA accumulation (145 +/- 22% of control). In contrast, hepatocytes exposed to ethanol exhibited only a slight elevation in CYP2E1 protein (122 +/- 13% of control) and a negligible effect on CYP4A11 protein. Clofibrate significantly (p < 0.05) enhanced both CYP4A11 mRNA and protein by 239 +/- 30% and 154 +/- 10% of control, respectively, but did not increase CYP2E1. Because rodent CYP4A is reportedly regulated by fatty acids through peroxisome proliferator activated receptor alpha (PPARalpha) and CYP2E1 is induced by high fat diets, we examined the effects of a medium chain fatty acid, palmitate on CYP2E1 mRNA content. Palmitic acid significantly (p < 0.05) increased CYP2E1 mRNA to 326 +/- 57% of control. Collectively, results presented here identify agents that enhance CYP2E1 and CYP4A11 at the transcription level and suggest that fatty acids may represent a similar mode of regulation for these P450 enzymes. The lack of induction of CYP2E1 protein by ethanol in human hepatocytes indicates that for certain P450 enzymes, isolated hepatocytes may not be an adequate tool for predicting in vivo responses.