PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators
PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators
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DOI：
10.1016/j.taap.2003.12.027
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发表时间：
2004-09-15
影响因子：
3.8
通讯作者：
Schuetz, EG
中科院分区：
文献类型：
--
作者：
Lamba, V;Yasuda, K;Schuetz, EG
为了深入了解胆甾烷X受体（PXR）的表达，我们分析了PXR。I和PXR选择性剪接转录本在一组36人组织。PXR. 1在比先前确定的更多的组织中表达，包括人类骨髓和人类大脑的选择区域。在这些组织中，我们观察到PXR的各种外显子的选择性剪接，产生多种不同的PXR亚型。最丰富的PXR替代mRNA转录物缺少111个核苷酸，从PXR LBD缺失37个氨基酸（PXR. 2），或缺少123个核苷酸，从PXR LBD缺失41个氨基酸（PXR. 3）。CYP 3A 4是一个受PXR转录调控的基因，其组织分布与PXR不完全重叠。人肝脏中PXR mRNA的定量表明，PXR. 2和PXR. 3分别占总PXR mRNA转录物的6.7%和0.32%。PXR的脑表达促使分析某些脑作用化学物质是否为PXR配体。神经甾体别孕烯醇酮和孕烯醇酮激活PXR并诱导CYP 3A 4-荧光素酶报告基因的转录。尼古丁是香烟中的精神活性和成瘾性化学物质，也是已知的脑CYP 2B 6诱导剂，是PXR的有效激活剂和CYP 3A 4转录的诱导剂。由于尼古丁激活PXR将增强尼古丁代谢为非精神活性的可替宁，因此这些结果为尼古丁耐受性的发展提供了一种分子机制。此外，PXR在许多人类组织（如脑）中的鉴定和组织特异性配体（如神经类固醇）的激活表明该受体在这些组织中的其他生物学作用。(C)2004年爱思唯尔公司All rights reserved.
To gain insight on the expression of pregnane X receptor (PXR), we analyzed PXR. I and PXR alternatively spliced transcripts in a panel of 36 human tissues. PXR.1 was expressed in many more tissues than previously determined, including human bone mar-row and select regions of the human brain. In each of these tissues, we observed alternative splicing of various exons of PXR that generated multiple distinct PXR isoforms. The most abundant PXR alternative mRNA transcripts lacked 111 nucleotides, deleting 37 amino acids from the PXR LBD (PXR.2), or lacked 123 nt, deleting 41 amino acids from the PXR LBD (PXR.3). CYP3A4, a gene transcriptionally regulated by PXR, showed incomplete overlap with PXR in its tissue distribution. Quantitation of PXR mRNAs in human liver demonstrated that PXR.2 and PXR.3 represented 6.7% and 0.32% of total PXR mRNA transcripts. Brain expression of PXR prompted analysis of whether some brain acting chemicals were PXR ligands. The neurosteroids allopregnanolone and pregnanolone activated PXR and induced transcription of a CYP3A4-luciferase reporter. Nicotine, the psychoactive and addictive chemical in cigarettes, and a known inducer of brain CYP2B6, was an efficacious activator of PXR and inducer of CYP3A4 transcription. Because nicotine activation of PXR will enhance metabolism of nicotine to the non-psychoactive cotinine, these results provide one molecular mechanism for the development of tolerance to nicotine. Moreover, the identification of PXR in many human tissues, such as brain, and activation by tissue specific ligands (such as neurosteroids) suggests additional biological roles for this receptor in these tissues. (C) 2004 Elsevier Inc. All rights reserved.