INDUCTION OF DETOXIFYING ENZYMES IN RODENT WHITE ADIPOSE TISSUE BY ARYL HYDROCARBON RECEPTOR AGONISTS AND ANTIOXIDANTS
INDUCTION OF DETOXIFYING ENZYMES IN RODENT WHITE ADIPOSE TISSUE BY ARYL HYDROCARBON RECEPTOR AGONISTS AND ANTIOXIDANTS
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DOI：
10.1124/dmd.105.007286
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发表时间：
2006-07
影响因子：
3.9
通讯作者：
K. Yoshinari;N. Okino;Takeshi Sato;J. Sugatani;M. Miwa
中科院分区：
文献类型：
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作者：
K. Yoshinari;N. Okino;Takeshi Sato;J. Sugatani;M. Miwa
肝脏是药物代谢的主要器官，但在肝外组织中也经常观察到外源性药物代谢酶的表达和诱导。最近，我们报道了亲脂性细胞色素P450诱导剂β-萘黄酮、苯巴比妥和地塞米松分别在基因和蛋白水平诱导大鼠附睾白脂肪组织细胞色素P450酶的表达。为了进一步证实外源生物诱导脂肪组织中药物代谢酶的表达，我们研究了芳烃受体激动剂和抗氧化剂对细胞色素P1A1等解毒酶的诱导作用。在大鼠的几个内脏器官(附睾管、肾周和肠系膜)中，BNF使细胞色素P1A1基因水平升高的程度大于皮下器官。利用对芳香烃有不同反应性的C57BL/6和DBA/2小鼠，并检测了AhR蛋白的胞浆水平，我们证明AhR在WAT中介导了BNF对CYP1A1的诱导。此外，核因子-E2相关因子2(NRF2)/抗氧化反应元件途径在WAT中也具有功能，因为已知激活AhR和NRF2的BNF以及包括叔丁基对苯二酚、1-氯-2，4-二硝基苯和甲苯二酮在内的抗氧化剂诱导大鼠和小鼠NRF2靶基因(NAD-(P)H：苯醌氧化还原酶、谷胱甘肽S转移酶A亚单位和血红素加氧酶-1)的表达。这些结果表明，AhR和Nrf2途径在WAT中都是活跃的，WAT中积累的亲脂化合物可以激活这些转录因子，提高组织的解毒能力。
The liver is the main organ of drug metabolism, but the expression and induction by xenobiotics of drug-metabolizing enzymes is also often observed in extrahepatic tissues. Recently, we reported that lipophilic cytochrome P450 inducers, β-naphthoflavone (BNF), phenobarbital, and dexamethasone, induced CYP1, CYP2B, and CYP3A enzymes, respectively, in rat epididymal white adipose tissue (WAT) at both mRNA and protein levels. To further confirm the xenobiotic-induced expression of drug-metabolizing enzymes in adipose tissue, we studied the induction of CYP1A1 and other detoxifying enzymes by aryl hydrocarbon receptor (AhR) agonists and antioxidants. BNF increased CYP1A1 mRNA levels in several visceral WATs (epididymal, perirenal, and mesenteric) to a greater degree than in subcutaneous WAT in rats. Using C57BL/6 and DBA/2 mice with different responsiveness to aryl hydrocarbons and detecting cytoplasmic levels of AhR proteins, we have demonstrated that AhR mediates this CYP1A1 induction by BNF in WAT. Moreover, the NF-E2-related factor 2 (Nrf2)/antioxidant responsive element pathway is also functional in WAT, since BNF, which is known to activate both AhR and Nrf2, and antioxidants including tert-butylhydroquinone, 1-chloro-2,4-dinitrobenzene, and menadione induced the expression of Nrf2-target genes (NAD-(P)H:quinone oxidoreductase, glutathione S-transferase A subunits, and heme oxygenase-1) in rats and mice. These results suggest that both AhR and Nrf2 pathways are active in WAT and that lipophilic compounds accumulated in WAT can activate these transcription factors to increase detoxification capability in the tissue.