Xenobiotic- and vitamin D-responsive induction of the steroid/bile acid-sulfotransferase Sult2A1 in young and old mice: The role of a gene enhancer in the liver chromatin
Xenobiotic- and vitamin D-responsive induction of the steroid/bile acid-sulfotransferase Sult2A1 in young and old mice: The role of a gene enhancer in the liver chromatin
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DOI：
10.1016/j.gene.2006.10.006
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发表时间：
2007-01-15
期刊：
影响因子：
3.5
通讯作者：
Chatterjee, Bandana
中科院分区：
文献类型：
--
作者：
Seo, Young-Kyo;Chung, Yoon-Tae;Chatterjee, Bandana
外源性激活的核受体PXR（雄烷X受体）和CAR（组成型雄烷受体）和维生素D-3激活的核受体VDR通过诱导I相细胞色素P450单加氧酶、II相缀合转移酶和III相转运蛋白来调节类固醇和外源性代谢，这些转运蛋白介导水溶性脂质代谢物从细胞中流出。已知由于类固醇和异生物质代谢酶的异常表达引起的代谢应激具有严重的健康后果，包括加速衰老，并且这些酶的表达增加与寿命延长相关[Gachon，F，Olela，FF，Schaad，O，Descombes，P和Schibler，U，2006.昼夜节律PAR结构域碱性亮氨酸拉链转录因子DBP、TEE和HLF调节基础和诱导性异生物质解毒。4，25-36。McElwee，JJ，Schuster，E，Blanc，E，托马斯，JH和Gems，D，2004年。秀丽隐杆线虫Dauer幼虫和长寿daf-2突变体中的共享转录特征涉及长寿保证中的去铁蛋白系统。J. Biol. Chem.，279，44533-43.]。通过研究类固醇和外源性物质代谢相关基因的衰老调节，可以揭示年轻人和老年人药物代谢的相似性和差异性，这可能具有临床意义。在这份报告中，我们研究了VDR和PXR介导的基因诱导的第二阶段磺基转移酶Sult 2Al在4个月和20个月大的小鼠的肝脏。Sult 2Al将胆汁酸、类固醇和许多药物转化为相应的硫酸化代谢物，由于水溶性增加，这些代谢物很容易从体内消除。在RT-PCR测定中，老化并没有改变由具有生物活性的维生素D-3和分解毒性的合成类固醇PCN（双烯醇酮-16 α-甲腈）对Sult 2Al mRNA的诱导。来自肝核的染色质免疫沉淀（ChIP）显示，在注射D-3或PCN的小鼠中，衰老对Sult 2Al染色质中的IR 0增强子募集VDR、RXR-α（类维生素A X受体）和PXR的活性没有影响。因此，晚年的小鼠与早期的小鼠一样有能力响应Sult 2Al诱导的激素和异生素信号。这是第一份报告描述的作用，在肝染色质增强核受体依赖性信号的功能反应的老化。(c)2006 Elsevier B. V.保留所有权利。
The xenobiotic-activated nuclear receptors PXR (pregnane X receptor) and CAR (constitutive androstane receptor) and the vitamin D-3-activated nuclear receptor VDR regulate steroid and xenobiotic metabolism by inducing the phase I cytochrome P450 monooxygenases, phase II conjugating transferases, and the phase III transporters, which mediate the efflux of water-soluble lipid metabolites from cells. Metabolic stress due to the deviant expression of steroid- and xenobiotic-metabolizing enzymes is known to have severe health consequences including accelerated aging, and increased expression of these enzymes is associated with extended longevity [Gachon, F, Olela, FF, Schaad, O, Descombes, P and Schibler, U, 2006. The circadian PAR-domain basic leucine zipper transcription factors DBP, TEE, and HLF modulate basal and inducible xenobiotic detoxification. 4, 25-36.; McElwee, JJ, Schuster, E, Blanc, E, Thomas, JH and Gems, D, 2004. Shared Transcriptional Signature in Caenorhabditis elegans Dauer Larvae and Long-lived daf-2 Mutants Implicates Detoxification System in Longevity Assurance. J. Biol. Chem., 279, 44533-43.]. Information on the similarities and dissimilarities in drug metabolism between the young and old, as may be uncovered by studying aging regulation of the genes relevant to steroid and xenobiotic metabolism, is likely to have clinical significance. In this report, we examined the VDR- and PXR-mediated gene induction of the phase II sulfotransferase Sult2Al in the livers of 4-month- and 20-month-old mice. Sult2Al converts bile acids, steroids and a number of drugs to the corresponding sulfated metabolites, which are readily eliminated from the body due to increased water solubility. In RT-PCR assay, aging did not change the induction of Sult2Al mRNAs by the hormonally active vitamin D-3 and the catatoxic synthetic steroid PCN (pregnenolone-16 alpha-carbonitrile). Chromatin immunoprecipitation (ChlP) from liver nuclei showed that aging had no effect on the activity of an IR0 enhancer in the Sult2Al chromatin to recruit VDR, RXR-alpha (retinoid X receptor) and PXR in mice injected with D-3 or PCN. Thus, mice in late life are as competent as those in early life in responding to the hormonal and xenobiotic signaling for Sult2Al induction. This is the first report describing the role of aging in the functional response of an enhancer in the liver chromatin to the nuclear receptor-dependent signaling. (c) 2006 Elsevier B.V. All rights reserved.