喹烯酮致HepG2细胞毒性与凋亡的分子调控机理研究
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摘要
喹烯酮(Quinocetone)属喹噁啉-1,4-二氧化物,是我国首创的一类新兽药,具有抗菌、止泻和促生长作用,目前己广泛应用于养猪业中。同类药物中的卡巴氧和喹乙醇由于具有遗传毒性和潜在的致癌作用,己被世界上许多国家禁止或限用做动物饲料添加剂。具有相同母核结构的喹烯酮体内外实验均显示出一定的遗传毒性,但其毒性作用机理仍不清楚。本研究以体外培养的具有代谢酶活性的人肝癌HepG2细胞为模型,研究喹烯酮的细胞毒性作用及其产生机制,分析喹烯酮对HepG2细胞全基因组表达谱的影响,探讨喹烯酮诱导HepG2细胞凋亡的分子调控机理,为评估喹烯酮对食品动物和人的安全性提供理论依据。
MTT试验结果表明喹烯酮能抑制HepG2细胞的增殖,24h和48h的IC50值分别为9.2μg/ml和6.7μg/ml。LDH释放试验显示喹烯酮能促使HepG2释放乳酸脱氢酶。流式细胞术检测发现喹烯酮对HepG2细胞具有显著的周期阻滞作用,低浓度喹烯酮使细胞阻滞于S期,高浓度时阻滞于Go/G1期。普通光学显微镜观察、Hoechst33342/PI染色观察及Annexin V-FITC/PI双染法流式检测结果表明喹烯酮能够诱导HepG2细胞凋亡。MDC染色、透射电子显微镜观察和流式细胞术检测证明喹烯酮诱导HepG2细胞发生自噬。以上结果表明喹烯酮具有明显的细胞毒性作用。
应用特异性荧光染料DCFH-DA和DHE检测喹烯酮处理HepG2细胞内ROS含量的变化,结果表明喹烯酮能呈剂量依赖性地诱导细胞内ROS含量增加。同时,细胞免疫化学方法检测到喹烯酮染毒细胞内DNA氧化损伤标志物-8-OHdG的含量增加。抗氧化剂NAC和GSH能够降低喹烯酮诱导的ROS含量升高,提高药物染毒细胞的活力,缓解喹烯酮所致线粒体膜电位的下降,显著抑制喹烯酮诱导的细胞凋亡。Western Blot试验结果显示NAC能够抑制Caspase-8和-3、Bid及PARP-1前体蛋白的剪切以及Bax/Bcl-2比值的升高,对JNK和p38MAPK磷酸化水平也具有显著的抑制作用。表明喹烯酮的细胞毒性可能与氧化应激反应有关。
采用Agilent公司人全基因组表达谱芯片检测喹烯酮处理HepG2细胞全基因组表达谱的改变,共筛选出6202个表达差异基因,其中表达上调3909个,表达下调2293个。差异基因所属GO条目4877个,pathway条目903个。结果显示喹烯酮的细胞毒性作用涉及多种代谢和信号途径,包括：细胞代谢、细胞周期、DNA复制与损伤修复、细胞凋亡、氧化应激、MAPK通路、p53信号途径、mTOR信号通路等。其中,与细胞凋亡调控有关的差异基因分布于外源性和内源性凋亡途径中,涉及对DNA损伤与修复的调节和细胞增殖相关基因的转录调控。
最后,我们对喹烯酮诱导HepG2细胞凋亡的分子调控机理进行了研究。TUNEL法流式检测结果表明喹烯酮能使细胞DNA发生片段化。Western Blot、RT-PCR和Caspase活性检测结果显示,喹烯酮所致凋亡过程伴有Caspase-8、-9和-3的激活。流式检测结果也表明广泛性Caspase抑制剂及Caspase-3、8和-9特异性抑制剂显著地抑制喹烯酮诱导的细胞凋亡。线粒体凋亡途径相关试验研究结果发现,喹烯酮能使细胞线粒体膜电位下降,促进细胞色素C的释放,Bax mRNA和蛋白水平上升,Bcl-2mRNA和蛋白水平下降,PARP-1蛋白发生剪切；Western Blot结果显示TNFR1、TNF-α、Fas和FADD蛋白含量增加,Bid蛋白发生剪切。RT-PCR结果表明TfNFR1、 TNF-a和Fas的mRNA水平升高。TNFR1/Fc受体阻断剂能抑制喹烯酮诱导的细胞凋亡,表明死亡受体途径也参与调节喹烯酮诱导的细胞凋亡。Western Blot检测结果表明p53、p21、p-p38和p-JNK蛋白水平增加,参与对喹烯酮所致凋亡的调控。上述结果表明喹烯酮对HepG2细胞凋亡的调控过程涉及Caspase的激活,TNF-a和TNFR1的信号转导,Bcl-2家族蛋白的调节,以及p53,p38和JNK信号通路的参与。
综上所述,喹烯酮对HepG2细胞具有细胞毒性,产生机制可能与氧化应激有关,可影响细胞内多种代谢通路,通过线粒体和死亡受体途径诱导细胞凋亡。
Quinocetone, a new quinoxaline1,4-dioxide derivative with antimicrobial, antidiarrhea and growth-promoting efficacy, has been classified as China's first class of new veterinary drug and widely used in swine industry. Similar drugs, such as carbadox and olaquindox, due to their genotoxic and potentially carcinogenic effects, have been banned or restricted to use as feed additives in many countries around the world. Having the same core chemical structure, quinocetone showed genetic toxicity in vivo and in vitro, but its mechanism of toxicity was still unclear. In this study, human hepatoma HepG2cells with the metabolic activity in vitro were used as a model to study quinocetone's toxicity and its mechanism of action, analyze quinocetone'impact on the genome-wide expression profiling of HepG2cells and investigate the molecular mechanisms regulating quinocetone-induced apoptosis in HepG2cells, in order to provide a theoretical basis for assessing the safety of quinocetone for food animals and human.
MTT results showed quinocetone inhibited the proliferation of HepG2cells. Its IC50values for24h and48h were9.2μg/ml and6.7μg/ml, respectively. LDH release assay indicated quinocetone could induce the release of lactate dehydrogenase from HepG2cells. Flow cytometry found quinocetone significantly arrested cell cycle and low concentrations of quinocetone arrested cells in S phase, while high concentrations of quinocetone arrested cells in G0/G1phase. Quinocetone-induced apoptosis in HepG2cells were confirmed using optical microscope observation, Hoechst33342/PI staining and Annexin V-FITC/PI double staining methods. The results of MDC staining, transmission electron microscopy and flow cytometry proved quinocetone induced autophagy in HepG2cells. All the above results suggested that quinocetone was cytotoxic.
Using specific fluorescent dyes DCFH-DA and DHE to detect intracellular ROS level changes, the results showed quinocetone increased the intracellular ROS levels in a dose-dependent manner. Simultaneously, the increased levels of8-OHdG, an intracellular oxidative DNA damage marker, were detected using immunocytochemistry after quinocetone exposure. NAC and GSH reduced ROS levels, improved the vitality of the cells, eased the disruption of mitochondrial membrane potential and inhibited quinocetone-induced apoptosis. Western blotting results showed NAC inhibited the cleavage of Caspase-8, Caspase-3, Bid and PARP-1precursor proteins, the elevation of Bax/Bcl-2ratio, as well as the phosphorylation levels of JNK and p38MAPK. These results showed quinocetone's cytotoxicity might be related to oxidative stress in HepG2cells.
Utilizing the whole human genome microarray of Agilent company to detect genome-wide expression profiling changes of HepG2cells treated with quinocetone, data showed there were6202differentially expressed genes, including3909upregulated genes and2293downregulated genes. These genes belonged to4877GO entries and903pathway entries. The results showed that quinocetone's cytotoxicity involved a variety of metabolic and signaling pathways, including cell metabolism, cell cycle, DNA replication and repair, apoptosis, oxidative stress, MAPK pathway, p53signaling pathway, mTOR signaling pathway, et al.. Among them, the apoptosis-related differentially expressed genes were categorized into the extrinsic and intrinsic apoptosis pathways, and also involved in the regulation of DNA damage and repair as well as cell proliferation-related gene transcription.
Finally, the molecular regulation mechanisms of apoptosis in quinocetone-treated HepG2cells were studied. TUNEL assay results showed quinocetone caused DNA fragmentation. Activation of Caspase-8,-9and-3in quinocetone-induced apoptosis were detected by Western blotting, RT-PCR and caspase activity assay. Flow cytometry results also showed pan caspase inhibitor and Caspase-3,-8and-9specific inhibitors significantly inhibited quinocetone-induced apoptosis. The mitochondrial apoptotic pathway relevant assay results found quinocetone disrupted mitochondrial membrane potential, promoted the release of cytochrome C, upregulated the mRNA and protein levels of Bax, downregulated the mRNA and protein levels of Bcl-2, and cleaved PARP-1protein. Western blotting results showed that TNFR1, TNF-a, Fas and FADD protein contents were increased and Bid was cleaved. The elevated mRNA levels of TNFR1, TNF-a and Fas were determined by RT-PCR. TNFRl/Fc chimera inhibited quinocetone-induced apoptosis, indicating that the death receptor pathway was also involved in the regulation of quinocetone-induced apoptosis. The protein levels of p53, p21, p-p38and p-JNK were increased, indicating their involvement in the regulation of quinocetone-induced apoptosis. Taken together, quinocetone induced apoptosis in HepG2cells via activation of caspase, interaction of TNF-a and TNFR1, modulation of the protein levels of Bid, Bax and Bcl-2, and involvement of the regulation of p53, p38and JNK.
In summary, quinocetone was cytotoxic to HepG2cells. The mechanism of quinocetone-induced cytotoxicity might be associated with oxidative stress. Quinocetone affected a variety of metabolic pathways within HepG2cells and induced apoptosis through mitochondrial and death receptor pathway.
MTT试验结果表明喹烯酮能抑制HepG2细胞的增殖,24h和48h的IC50值分别为9.2μg/ml和6.7μg/ml。LDH释放试验显示喹烯酮能促使HepG2释放乳酸脱氢酶。流式细胞术检测发现喹烯酮对HepG2细胞具有显著的周期阻滞作用,低浓度喹烯酮使细胞阻滞于S期,高浓度时阻滞于Go/G1期。普通光学显微镜观察、Hoechst33342/PI染色观察及Annexin V-FITC/PI双染法流式检测结果表明喹烯酮能够诱导HepG2细胞凋亡。MDC染色、透射电子显微镜观察和流式细胞术检测证明喹烯酮诱导HepG2细胞发生自噬。以上结果表明喹烯酮具有明显的细胞毒性作用。
应用特异性荧光染料DCFH-DA和DHE检测喹烯酮处理HepG2细胞内ROS含量的变化,结果表明喹烯酮能呈剂量依赖性地诱导细胞内ROS含量增加。同时,细胞免疫化学方法检测到喹烯酮染毒细胞内DNA氧化损伤标志物-8-OHdG的含量增加。抗氧化剂NAC和GSH能够降低喹烯酮诱导的ROS含量升高,提高药物染毒细胞的活力,缓解喹烯酮所致线粒体膜电位的下降,显著抑制喹烯酮诱导的细胞凋亡。Western Blot试验结果显示NAC能够抑制Caspase-8和-3、Bid及PARP-1前体蛋白的剪切以及Bax/Bcl-2比值的升高,对JNK和p38MAPK磷酸化水平也具有显著的抑制作用。表明喹烯酮的细胞毒性可能与氧化应激反应有关。
采用Agilent公司人全基因组表达谱芯片检测喹烯酮处理HepG2细胞全基因组表达谱的改变,共筛选出6202个表达差异基因,其中表达上调3909个,表达下调2293个。差异基因所属GO条目4877个,pathway条目903个。结果显示喹烯酮的细胞毒性作用涉及多种代谢和信号途径,包括：细胞代谢、细胞周期、DNA复制与损伤修复、细胞凋亡、氧化应激、MAPK通路、p53信号途径、mTOR信号通路等。其中,与细胞凋亡调控有关的差异基因分布于外源性和内源性凋亡途径中,涉及对DNA损伤与修复的调节和细胞增殖相关基因的转录调控。
最后,我们对喹烯酮诱导HepG2细胞凋亡的分子调控机理进行了研究。TUNEL法流式检测结果表明喹烯酮能使细胞DNA发生片段化。Western Blot、RT-PCR和Caspase活性检测结果显示,喹烯酮所致凋亡过程伴有Caspase-8、-9和-3的激活。流式检测结果也表明广泛性Caspase抑制剂及Caspase-3、8和-9特异性抑制剂显著地抑制喹烯酮诱导的细胞凋亡。线粒体凋亡途径相关试验研究结果发现,喹烯酮能使细胞线粒体膜电位下降,促进细胞色素C的释放,Bax mRNA和蛋白水平上升,Bcl-2mRNA和蛋白水平下降,PARP-1蛋白发生剪切；Western Blot结果显示TNFR1、TNF-α、Fas和FADD蛋白含量增加,Bid蛋白发生剪切。RT-PCR结果表明TfNFR1、 TNF-a和Fas的mRNA水平升高。TNFR1/Fc受体阻断剂能抑制喹烯酮诱导的细胞凋亡,表明死亡受体途径也参与调节喹烯酮诱导的细胞凋亡。Western Blot检测结果表明p53、p21、p-p38和p-JNK蛋白水平增加,参与对喹烯酮所致凋亡的调控。上述结果表明喹烯酮对HepG2细胞凋亡的调控过程涉及Caspase的激活,TNF-a和TNFR1的信号转导,Bcl-2家族蛋白的调节,以及p53,p38和JNK信号通路的参与。
综上所述,喹烯酮对HepG2细胞具有细胞毒性,产生机制可能与氧化应激有关,可影响细胞内多种代谢通路,通过线粒体和死亡受体途径诱导细胞凋亡。
Quinocetone, a new quinoxaline1,4-dioxide derivative with antimicrobial, antidiarrhea and growth-promoting efficacy, has been classified as China's first class of new veterinary drug and widely used in swine industry. Similar drugs, such as carbadox and olaquindox, due to their genotoxic and potentially carcinogenic effects, have been banned or restricted to use as feed additives in many countries around the world. Having the same core chemical structure, quinocetone showed genetic toxicity in vivo and in vitro, but its mechanism of toxicity was still unclear. In this study, human hepatoma HepG2cells with the metabolic activity in vitro were used as a model to study quinocetone's toxicity and its mechanism of action, analyze quinocetone'impact on the genome-wide expression profiling of HepG2cells and investigate the molecular mechanisms regulating quinocetone-induced apoptosis in HepG2cells, in order to provide a theoretical basis for assessing the safety of quinocetone for food animals and human.
MTT results showed quinocetone inhibited the proliferation of HepG2cells. Its IC50values for24h and48h were9.2μg/ml and6.7μg/ml, respectively. LDH release assay indicated quinocetone could induce the release of lactate dehydrogenase from HepG2cells. Flow cytometry found quinocetone significantly arrested cell cycle and low concentrations of quinocetone arrested cells in S phase, while high concentrations of quinocetone arrested cells in G0/G1phase. Quinocetone-induced apoptosis in HepG2cells were confirmed using optical microscope observation, Hoechst33342/PI staining and Annexin V-FITC/PI double staining methods. The results of MDC staining, transmission electron microscopy and flow cytometry proved quinocetone induced autophagy in HepG2cells. All the above results suggested that quinocetone was cytotoxic.
Using specific fluorescent dyes DCFH-DA and DHE to detect intracellular ROS level changes, the results showed quinocetone increased the intracellular ROS levels in a dose-dependent manner. Simultaneously, the increased levels of8-OHdG, an intracellular oxidative DNA damage marker, were detected using immunocytochemistry after quinocetone exposure. NAC and GSH reduced ROS levels, improved the vitality of the cells, eased the disruption of mitochondrial membrane potential and inhibited quinocetone-induced apoptosis. Western blotting results showed NAC inhibited the cleavage of Caspase-8, Caspase-3, Bid and PARP-1precursor proteins, the elevation of Bax/Bcl-2ratio, as well as the phosphorylation levels of JNK and p38MAPK. These results showed quinocetone's cytotoxicity might be related to oxidative stress in HepG2cells.
Utilizing the whole human genome microarray of Agilent company to detect genome-wide expression profiling changes of HepG2cells treated with quinocetone, data showed there were6202differentially expressed genes, including3909upregulated genes and2293downregulated genes. These genes belonged to4877GO entries and903pathway entries. The results showed that quinocetone's cytotoxicity involved a variety of metabolic and signaling pathways, including cell metabolism, cell cycle, DNA replication and repair, apoptosis, oxidative stress, MAPK pathway, p53signaling pathway, mTOR signaling pathway, et al.. Among them, the apoptosis-related differentially expressed genes were categorized into the extrinsic and intrinsic apoptosis pathways, and also involved in the regulation of DNA damage and repair as well as cell proliferation-related gene transcription.
Finally, the molecular regulation mechanisms of apoptosis in quinocetone-treated HepG2cells were studied. TUNEL assay results showed quinocetone caused DNA fragmentation. Activation of Caspase-8,-9and-3in quinocetone-induced apoptosis were detected by Western blotting, RT-PCR and caspase activity assay. Flow cytometry results also showed pan caspase inhibitor and Caspase-3,-8and-9specific inhibitors significantly inhibited quinocetone-induced apoptosis. The mitochondrial apoptotic pathway relevant assay results found quinocetone disrupted mitochondrial membrane potential, promoted the release of cytochrome C, upregulated the mRNA and protein levels of Bax, downregulated the mRNA and protein levels of Bcl-2, and cleaved PARP-1protein. Western blotting results showed that TNFR1, TNF-a, Fas and FADD protein contents were increased and Bid was cleaved. The elevated mRNA levels of TNFR1, TNF-a and Fas were determined by RT-PCR. TNFRl/Fc chimera inhibited quinocetone-induced apoptosis, indicating that the death receptor pathway was also involved in the regulation of quinocetone-induced apoptosis. The protein levels of p53, p21, p-p38and p-JNK were increased, indicating their involvement in the regulation of quinocetone-induced apoptosis. Taken together, quinocetone induced apoptosis in HepG2cells via activation of caspase, interaction of TNF-a and TNFR1, modulation of the protein levels of Bid, Bax and Bcl-2, and involvement of the regulation of p53, p38and JNK.
In summary, quinocetone was cytotoxic to HepG2cells. The mechanism of quinocetone-induced cytotoxicity might be associated with oxidative stress. Quinocetone affected a variety of metabolic pathways within HepG2cells and induced apoptosis through mitochondrial and death receptor pathway.
引文
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