Comparison of pulmonary/nasal CYP2F expression levels in rodents and rhesus macaque
Comparison of pulmonary/nasal CYP2F expression levels in rodents and rhesus macaque
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DOI：
10.1124/jpet.103.062901
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发表时间：
2004-04-01
影响因子：
3.5
通讯作者：
Buckpitt, AR
中科院分区：
文献类型：
--
作者：
Baldwin, RM;Jewell, WT;Buckpitt, AR
萘是一种普遍存在的环境污染物，接触后会导致小鼠 Clara 细胞出现剂量依赖性、组织、物种和细胞选择性坏死。萘被 CYP2F 代谢为 1,2-环氧化物，这是导致细胞毒性的第一步，也是必然的一步。本文报道的研究检查了啮齿类动物呼吸道中转录物 (mRNA) 和 CYP2F 蛋白水平与组织损伤易感性之间的关系。在小鼠和大鼠中，肺部比肝脏含有更多的 CYP2F 转录物；肾脏中的水平检测不到。小鼠在肺和肝组织中表达的 CYP2F 转录本分别是大鼠的 4 倍和 8 倍。气道亚室中 CYP2F 的定量免疫印迹分析显示，小鼠的 CYP2F 蛋白水平比大鼠高 30 倍（小子体/终末细支气管）、20 倍（大子体）、40 倍（气管）和 6 倍（实质）。在两种啮齿类动物的肺部内，CYP2F 表达最高的区域是远端气道。肾脏中含有检测不到的 CYP2F；肝脏中的多个免疫反应带妨碍了定量。在大鼠研究的所有组织中，嗅上皮含有最多数量的细胞色素 P450 蛋白，这与观察到的体内损伤模式一致。总体而言，这些在啮齿动物中的研究表明 CYP2F 表达水平与萘诱导的细胞毒性的易感性之间存在密切关联。在所有研究的灵长类组织中，只有鼻鼻甲酸盐含有可定量的 CYP2F，分别比大鼠和小鼠的相应组织少大约 10 倍和 20 倍。这些结果表明恒河猴可能对萘引起的肺损伤具有抵抗力。
Naphthalene is a ubiquitous environmental contaminant that results in dose-dependent and tissue-, species-, and cell-selective necrosis of murine Clara cells upon exposure. Naphthalene is metabolized by CYP2F to a 1,2-epoxide, the first and obligate step in events leading to cytotoxicity. The studies reported here examine the relationship between levels of transcript (mRNA) and CYP2F protein in the respiratory tract of rodents with tissue susceptibility to injury. In both mice and rats, the lung contains more CYP2F transcript than liver; levels in kidney were undetectable. Mice expressed 4- and 8-fold greater CYP2F transcript in lung and liver tissue, respectively, than rats. Quantitative immunoblot blot analysis of CYP2F in airway subcompartments revealed mice to have 30-(minor daughters/terminal bronchioles), 20-(major daughter), 40-(trachea), and 6-(parenchyma) fold higher levels of CYP2F protein than rats. Within the lungs of both rodent species, the highest CYP2F expression was found in the distal airways. The kidney contained undetectable amounts of CYP2F; multiple immunoreactive bands in liver precluded quantification. The olfactory epithelium contains the greatest amount of cytochrome P450 protein of all tissues studied in the rat, consistent with the observed pattern of in vivo injury. Overall, these studies in rodents demonstrate a strong association between CYP2F expression levels and susceptibility to naphthalene-induced cytotoxicity. Of all primate tissues studied, only the nasal ethmoturbinates contain quantifiable amounts of CYP2F, roughly 10- and 20-fold less than the corresponding tissues in rats and mice, respectively. These results suggest that rhesus macaques may be refractory to naphthalene-induced pulmonary injury.