Flavin-containing monooxygenase-3: induction by 3-methylcholanthrene and complex regulation by xenobiotic chemicals in hepatoma cells and mouse liver.
Flavin-containing monooxygenase-3: induction by 3-methylcholanthrene and complex regulation by xenobiotic chemicals in hepatoma cells and mouse liver.
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DOI：
10.1016/j.taap.2010.05.018
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发表时间：
2010-08-15
影响因子：
3.8
通讯作者：
Williams DE
中科院分区：
文献类型：
--
作者：
Celius T;Pansoy A;Matthews J;Okey AB;Henderson MC;Krueger SK;Williams DE
含有黄素的单加氧酶通常被认为是不可诱导的，但我们最近证明了2，3，7，8-四氯二苯并对二恶英(TCDD)对小鼠肝脏FMO mRNAs的诱导依赖于芳烃受体(AHR)。我们现在评估了其他AHR配体和异种化学物质在体内和在小鼠肝癌细胞(HEPA-1)中诱导FMO的作用。在小鼠肝脏中，3-甲基胆蒽(3MC)诱导FMO3mRNA表达增加8倍。在HEPA-1细胞中，3MC和苯并[a]芘(BaP)可诱导FMO3基因的表达增加30倍。3MC和BaP的诱导是AHR依赖的，但令人惊讶的是，强大的AHR激动剂TCDD不能在HEPA-1细胞中诱导Fmo3mRNA，染色质免疫沉淀试验也没有检测到3mc暴露于肝脏或HEPA-1细胞后AHR或Arnt对Fmo3调控元件的募集。然而，在HEPA-1中，3MC和BaP(但不是TCDD)导致P53蛋白募集到FMO3基因5‘侧翼区的P53反应元件。我们测试了Fmo3在HEPA-1细胞中诱导的可能性，可能是由Nrf2/抗氧化剂反应通路介导的，但已知的激活Nrf2或诱导氧化应激的药物不影响Fmo3的mRNA水平。蛋白质合成抑制剂放线菌酮(在TCDD处理的细胞中引起细胞色素P1A1基因的“超诱导”)本身就能引起HEPA-1细胞中FMO3基因表达的显著上调(>；300倍)，这表明放线菌素阻止了一种抑制FMO3表达的不稳定蛋白质的合成。3MC或TCDD可显著诱导小鼠肝脏和HEPA-1细胞FMO3mRNA的表达，但对FMO蛋白水平和FMO催化功能的影响不大。
Flavin-containing monooxygenases often are thought not to be inducible but we recently demonstrated aryl hydrocarbon receptor (AHR)-dependent induction of FMO mRNAs in mouse liver by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We now evaluated FMO induction by other AHR ligands and xenobiotic chemicals in vivo and in mouse Hepa1c1c7 hepatoma cells (Hepa-1). In mouse liver, 3-methylcholanthrene (3MC) induced FMO3 mRNA 8-fold. In Hepa-1 cells, 3MC and benzo[a]pyrene (BaP) induced FMO3 mRNA >30-fold. Induction by 3MC and BaP was AHR-dependent but, surprisingly, the potent AHR agonist, TCDD, did not induce FMO3 mRNA in Hepa-1 cells nor did chromatin immunoprecipitation assays detect recruitment of AHR or ARNT to Fmo3 regulatory elements after exposure to 3MC in liver or in Hepa-1 cells. However, in Hepa-1, 3MC and BaP (but not TCDD) caused recruitment of p53 protein to a p53 response element in the 5'-flanking region of the Fmo3 gene. We tested the possibility that FMO3 induction in Hepa-1 cells might be mediated by Nrf2/antioxidant response pathways but agents known to activate Nrf2 or to induce oxidative stress did not affect FMO3 mRNA levels. The protein synthesis inhibitor, cycloheximide (which causes “superinduction” of CYP1A1 mRNA in TCDD-treated cells) by itself caused dramatic upregulation (>300-fold) of FMO3 mRNA in Hepa-1 suggesting that cycloheximide prevents synthesis of a labile protein that suppresses FMO3 expression. Although FMO3 mRNA is highly induced by 3MC or TCDD in mouse liver and in Hepa-1 cells, FMO protein levels and FMO catalytic function showed only modest elevation.
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影响因子：
5.8
作者：
Koehle, Christoph;Bock, Karl Walter
通讯作者：
Bock, Karl Walter
影响因子：
3.6
作者：
Joiakim, A;Mathieu, PA;Reiners, JJ
通讯作者：
Reiners, JJ
影响因子：
5.8
作者：
Klick, David E.;Shadley, Jeff D.;Hines, Ronald N.
通讯作者：
Hines, Ronald N.
DOI：
10.1080/00984100290071054
发表时间：
2002-06-28
影响因子：
2.6
作者：
Hassoun, EA;Wang, H;Stohs, SJ
通讯作者：
Stohs, SJ
DOI：
10.1124/jpet.106.112268
发表时间：
2007-01-01
影响因子：
3.5
作者：
Koukouritaki, Sevasti B.;Poch, Mark T.;Hines, Ronald N.
通讯作者：
Hines, Ronald N.