Expression of cytochrome P-450 4 enzymes in the kidney and liver: Regulation by PPAR and species-difference between rat and human
Expression of cytochrome P-450 4 enzymes in the kidney and liver: Regulation by PPAR and species-difference between rat and human
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DOI：
10.1007/s11010-005-9038-x
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发表时间：
2006-03-01
影响因子：
4.3
通讯作者：
Kohzuki, M
中科院分区：
文献类型：
--
作者：
Ito, O;Nakamura, Y;Kohzuki, M
细胞色素P-450 4（CYP 4）家族的成员催化脂肪酸的ω-羟基化，并且其中一些在基因的启动子区域中具有PPAR反应元件。在大鼠肾脏和肝脏中测定了CYP 4A和PPAR亚型的定位以及PPAR激动剂对CYP 4A蛋白水平和活性的影响。免疫印迹分析显示，CYP 4A在肝脏和近曲小管中表达，在肾小球前微血管、肾小球和粗升支（TAL）中表达较低，而在集合管中未检测到表达。PPAR α在肝脏、近端小管和TAL中表达。PPAR γ在集合管中表达，在TAL中表达较低，但在近端小管和肝脏中无表达。PPAR α激动剂氯贝特可诱导肾皮质和肝脏中的CYP 4A蛋白水平和活性。在这些组织中，PPAR γ激动剂吡格列酮不调节它们。用免疫组化技术进一步确定了CYP 4A和CYP 4F在人肾和肝中的定位。在肝小叶和近端小管的肝细胞中观察到CYP 4A和CYP 4F的免疫染色，在TAL和集合管中染色较低，但在肾小球或肾血管中无染色。这些结果表明，在大鼠组织中的诱导CYP 4A的过氧化物酶体增殖物激活物受体激动剂与相应的过氧化物酶体增殖物激活物受体亚型的表达相关，和CYP 4在肾脏中的定位有一个物种之间的差异大鼠和人类。
Members of the cytochrome P-450 4 (CYP4) family catalyze the omega-hydroxylation of fatty acids, and some of them have the PPAR response element in the promoter area of the genes. The localization of CYP4A and PPAR isoforms and the effect of PPAR agonists on CYP4A protein level and activity were determined in rat kidney and liver. Immunoblot analysis showed that CYP4A was expressed in the liver and proximal tubule, with lower expression in the preglomerular microvessel, glomerulus and thick ascending limb (TAL), but the expression was not detected in the collecting duct. PPAR alpha was expressed in the liver, proximal tubule and TAL. PPAR gamma was expressed in the collecting duct, with lower expression in the TAL, but no expression in the proximal tubule and liver. The PPAR alpha agonist clofibrate induced CYP4A protein levels and activity in the renal cortex and liver. The PPAR gamma agonist pioglitazone did not modulate them in these tissues. The localization of CYP4A and CYP4F were further determined in human kidney and liver by immunohistochemical technique. Immunostainings for CYP4A and CYP4F were observed in the hepatocytes of the liver lobule and the proximal tubules, with lower stainings in the TALs and collecting ducts, but no staining in the glomeruli or renal vasculatures. These results indicate that the inducibility of CYP4A by PPAR agonists in the rat tissues correlates with the expression of the respective PPAR isoforms, and that the localization of CYP4 in the kidney has a species-difference between rat and human.