Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice.
Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice.
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DOI：
10.1016/j.toxlet.2008.12.014
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发表时间：
2009-03-28
影响因子：
3.5
通讯作者：
Kleiner, Heather E.
中科院分区：
文献类型：
--
作者：
Prince, Misty;Li, Yan;Childers, Asper;Ltoh, Ken;Yamamoto, Masayuki;Kleiner, Heather E.
天然香豆素具有抗癌活性，部分是通过诱导解毒酶谷胱甘肽S转移酶(GST)和(或)NAD(P)H-苯醌氧化还原酶(NQO1)实现的。我们的目标是确定柑橘香豆素是否通过激活Nrf2和抗氧化反应元件来诱导肝脏GST和/或NQO1。首先，稳定转染ARE和绿色荧光蛋白(GFP)报告基因的HepG2细胞被增加浓度的香豆素处理，并与阳性对照进行比较。叔丁基对苯二酚(TBHQ)和奥替拉兹以及香豆素、柠檬素、金鱼藤烯、欧前胡素和7，8-苯黄酮都能增强GFP的荧光，表明它们激活ARE，而异胡萝卜素不增加GFP的荧光。接下来，比较口服香豆素和奥替拉兹对表现出野生型表型的Nrf2基因敲除小鼠和Nrf2杂合子小鼠肝脏GST和NQO1活性的影响。OltiPraz、Auapene、欧前胡素、异胡萝卜素和Auapene均显著增加Nrf2杂合子小鼠肝细胞浆GST活性。这种作用在给药的Nrf2(−/−)小鼠中被取消，在Nrf2(−/−)小鼠中被Auapapene和欧前胡素处理的小鼠减弱，在Nrf2(−/−)小鼠中用异胡萝卜素处理仍然显著。在这些化合物中，只有异叶胡萝卜素显著增加肝脏胞浆NQO_1的活性，并且这种作用在Nrf2(−/−)小鼠身上没有减弱。这些结果有力地表明欧前胡素和Auapene通过Nrf2/ARE机制诱导小鼠肝细胞胞浆GST活性。虽然在结构上相似，但异胡萝卜素似乎不能激活HepG2-Are-GFP，Nrf2基因敲除小鼠的研究表明，异胡萝卜素可能通过其他机制诱导GST和NQO1。
Naturally occurring coumarins possess anti-carcinogenic activities in part by inducing carcinogen-detoxifying enzymes glutathione S-transferase (GST) and/or NAD(P)H quinone oxidoreductase (NQO1). Our goal was to determine whether citrus coumarins induce hepatic GST and/or NQO1 via activation of Nrf2 and the antioxidant response element. First, HepG2 cells stably transfected with the ARE and a green fluorescent protein (GFP) reporter were treated with increasing concentrations of coumarins and compared to positive controls. tert-butylhydroquinone (TBHQ) and oltipraz increased GFP fluorescence, as did coumarin, limettin, auraptene, imperatorin, and 7,8-benzoflavone, suggesting that they activate the ARE, whereas isopimpinellin did not increase GFP fluorescence. Next, the effects of orally-administered coumarins and oltipraz on hepatic GST and NQO1 activities were compared in Nrf2 knockout mice or Nrf2 heterozygous mice exhibiting the wild-type phenotype. Oltipraz, auraptene, imperatorin, isopimpinellin, and auraptene all significantly increased liver cytosolic GST activities in Nrf2 heterozygous mice. This effect was abrogated in Nrf2(−/−) mice dosed with oltipraz, attenuated in mice Nrf2(−/−) mice treated with auraptene and imperatorin, and still significant in Nrf2(−/−) mice treated with isopimpinellin. Of these compounds, only isopimpinellin significantly increased liver cytosolic NQO1 activities, and this effect was not attenuated in Nrf2(−/−) mice. These results strongly suggest that imperatorin and auraptene induce murine liver cytosolic GST activities via the Nrf2/ARE mechanism. Although structurally similar, isopimpinellin did not appear to activate HepG2-ARE-GFP and the Nrf2 knockout mouse study suggests that isopimpinellin may induce GST and NQO1 via additional mechanisms.
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影响因子：
4.7
作者：
Langouet, S;Maheo, K;Guillouzo, A
通讯作者：
Guillouzo, A
DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Holtzclaw, WD;Talalay, P
通讯作者：
Talalay, P
影响因子：
3.5
作者：
Campbell, Cheryl T.;Prince, Misty;Kleiner, Heather E.
通讯作者：
Kleiner, Heather E.
影响因子：
4.7
作者：
Kleiner, HE;Vulimiri, SV;DiGiovanni, J
通讯作者：
DiGiovanni, J
影响因子：
4.1
作者：
Kleiner, HE;Vulimiri, SV;DiGiovanni, J
通讯作者：
DiGiovanni, J