The flavonoids diosmetin and luteolin exert synergistic cytostatic effects in human hepatoma HepG2 cells via CYP1A-catalyzed metabolism, activation of JNK and ERK and P53/P21 up-regulation
The flavonoids diosmetin and luteolin exert synergistic cytostatic effects in human hepatoma HepG2 cells via CYP1A-catalyzed metabolism, activation of JNK and ERK and P53/P21 up-regulation
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DOI：
10.1016/j.jnutbio.2012.01.012
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发表时间：
2013-02-01
影响因子：
5.6
通讯作者：
Spandidos, Demetrios A.
中科院分区：
文献类型：
--
作者：
Androutsopoulos, Vasilis P.;Spandidos, Demetrios A.
已知各种类型的肿瘤过度表达属于细胞色素P450的CYP 1家族的酶。本研究旨在表征天然黄酮类化合物薯蓣皂苷在表达CYP 1的人肝癌细胞系HepG 2中的代谢和进一步的抗增殖活性。Diosmetin在HepG 2细胞中孵育12和30 h后转化为木犀草素。在存在CYP 1A抑制剂α-萘甲酮的情况下，薯蓣皂苷向毛地黄黄酮的转化减弱。3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四唑溴化物测定显示木樨草素比地奥司汀具有更强的细胞毒性。流式细胞仪检测表明，薯蓣皂苷对HepG 2细胞的增殖抑制作用主要是通过阻滞G2/M期细胞而实现的。G2/M期阻滞的诱导伴随着磷酸化细胞外信号调节激酶（p-ERK）、磷酸化c-jun N-末端激酶、p53和p21蛋白的上调。更重要的是，诱导G2/M期阻滞和p53和p-ERK上调被逆转的应用CYP 1抑制剂α-萘甲酮。总之，这些数据提供了细胞色素P450 CYP 1A酶的肿瘤抑制作用的新证据，并扩展了膳食黄酮类化合物的抗癌活性通过P450活化而增强的假设。(C)2013 Elsevier Inc. All rights reserved.
Various types of tumors are known to overexpress enzymes belonging to the CYP1 family of cytochromes P450. The present study aimed to characterize the metabolism and further antiproliferative activity of the natural flavonoid diosmetin in the CYP1-expressing human hepatoma cell line HepG2. Diosmetin was converted to luteolin in HepG2 cells after 12 and 30 h of incubation. In the presence of the CYP1A inhibitor alpha-naphthoflavone, the conversion of diosmetin to luteolin was attenuated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed luteolin to be more cytotoxic than diosmetin. The antiproliferative effect of diosmetin in HepG2 cells was attributed to blockage at the G2/M phase as determined by flow cytometry. Induction of G2/M arrest was accompanied by up-regulation of phospho-extracellular-signal-regulated kinase (p-ERK), phospho-c-jun N-terminal kinase, p53 and p21 proteins. More importantly, induction of G2/M arrest and p53 and p-ERK up-regulation were reversed by the application of the CYP1 inhibitor alpha-naphthoflavone. Taken together, the data provide new evidence on the tumor-suppressing role of cytochrome P450 CYP1A enzymes and extend the hypothesis that the anticancer activity of dietary flavonoids is enhanced by P450-activation. (C) 2013 Elsevier Inc. All rights reserved.