CAR and PXR expression and inducibility of CYP2B and CYP3A activities in rat and rabbit lungs
CAR and PXR expression and inducibility of CYP2B and CYP3A activities in rat and rabbit lungs
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DOI：
10.1016/j.lfs.2004.09.042
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发表时间：
2005-04-15
期刊：
影响因子：
6.1
通讯作者：
Gervasi, PG
中科院分区：
文献类型：
--
作者：
Chirulli, V;Longo, V;Gervasi, PG
哺乳动物的肺中表达了几种CYP酶，但对其调控的研究一直被忽视。本研究观察了Car和PXR在大鼠和兔肺组织中的表达及其对CYP 2B和CYP 3A亚型的诱导作用。大鼠接受苯巴比妥、克霉唑或地塞米松+孕烯醇酮16α-碳酸酯的混合物治疗，而兔子接受苯巴比妥或利福平治疗。RT-PCR分析显示CAR基因在大鼠肺组织中低表达，而在兔肺组织中不表达。通过蛋白质印迹分析和标记的戊氧基间苯二酚O-脱烷基酶和7-乙氧基-4-三氟乙基香豆素O-脱乙基酶活性判断，苯巴比妥治疗没有改变CAR的表达谱，也没有诱导大鼠和兔肺组织中的CYP 2B亚型。相反，苯巴比妥在两种动物的肝脏中强烈地诱导了这些标志物的活性。RT-PCR在兔肺组织中也检测到低组成水平的PXR基因，而在大鼠肺组织中未检测到。然而，同样在这种情况下，它们的表达不会被强的CyP3A诱导剂如克霉唑或地塞米松与孕烯醇酮16α-碳腈的混合物(对大鼠)和利福平或苯巴比妥(对兔)的注射改变。首次通过RT-PCR证实大鼠肺表达3A2、3A9、3A18和3A23，而兔肺表达3A6，这是唯一的3A亚型。到目前为止在兔子身上发现了这种病毒。然而，尽管在两个物种中观察到PXR和CYP3A转录本的组成存在差异，但上述处理并不影响它们的肺，不同于它们的肝脏，既不影响抗大鼠3A免疫反应蛋白，也不影响CYP3A标记7-苄氧基喹啉O-脱苄基酶和6-β-睾酮羟基酶的活性。这些结果表明，Car和PXR在大鼠和兔肺中的作用不同于在肝脏或其他肝外组织中观察到的作用。在肝脏或其他肝外组织中，CYP 2B和CYP3A亚型的诱导受这些受体的调节。(C)2005 Elsevier Inc.保留所有权利。
Several CYP enzymes are expressed in the lung of mammals but studies on their regulation have been rather neglected. In this study, the CAR and PXR expression and the inducibility of CYP 2B and CYP 3A isoforms in the lung rats and rabbits were investigated. Rats were treated with phenobarbital, clotrimazole or a mixture of dexametasone plus pregnenolone 16 alpha-carbonittile, whereas rabbits were treated with phenobarbital or rifampicin. A low constitutive expression of CAR mRNA was demonstrated by RT-PCR analysis in the lung of rat but not in rabbit. Phenobarbital treatment did not change the CAR expression profiles and did not induce in either rats and rabbits the pulmonary CYP 2B isoforms, as judged by western blot analysis and the marker pentoxyresorufin O-dealkylase and 7-ethoxy-4-trifluoroethylcoumarin O-deethylase activities. On the contrary, these marker activities were strongly induced by phenobarbital in the liver of both species. A low constitutive level of PXR mRNA was also detected by RT-PCR in the lung of rabbit but not in rat. However, also in this case, their expressions were not altered by the administration of strong CYP 3A inducers such as clotrimazole or a mixture of dexametasone plus pregnenolone 16 alpha-carbonitrile for the rat and rifampicin or phenobarbital for the rabbit. For the first time, it was demonstrated by RT-PCR that rat lung expresses CYP 3A2, 3A9, 3A18 and 3A23 whereas the rabbit lung expresses the CYP 3A6, the only CYP 3A isoform. identified in the rabbit so far. However, notwithstanding the differences observed in the constitutive presence of PXR and CYP 3A transcripts in both species, the above mentioned treatments did not affect in their lungs, unlike their livers, neither the anti-rat 3A immunoreactive proteins nor the CYP 3A marker 7-benzyloxyquinoline O-debenzylase and the 6 beta-testosterone hydroxylase activities. The results obtained indicate that the role of CAR and PXR in the lung of rat and rabbit is different that observed in the liver or other extrahepatic tissues where the induction of the CYP 2B and CYP 3A isoforms is regulated by these receptors. (c) 2005 Elsevier Inc. All rights reserved.