CYP2E1酶在去甲斑蝥素代谢和环孢素诱导肝损伤中的作用研究
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摘要
细胞色素P450酶2E1亚型(CYP2E1酶)可介导多种体内、外源性化合物代谢,在药理学和毒理学研究方面作用十分重要,本研究以去甲斑蝥素和环孢素为切入点,分别对CYP2E1酶在药物代谢和药物性肝损伤发病过程中的作用进行探讨。
去甲斑蝥素用于肿瘤治疗多年,但其体内代谢过程尚未完全清楚。本研究首先采用MetaPrint2D软件,根据去甲斑蝥素及其水解产物去甲斑蝥酸化学结构中原子指纹特征,基于数据挖掘和统计分析技术,通过计算原子作为代谢位点的发生率,预测去甲斑蝥素及其代谢物去甲斑蝥酸代谢位点及可能代谢产物；采用Sybyl软件分别进行CYP1A2, CYP2A6, CYP2B6, CYP3A4, CYP2D6, CYP2C9, CYP2E1和CYP2C19酶与去甲斑蝥酸对接；然后选择其中得分较高者,进行人重组CYP450酶体外代谢实验,结果显示,CYP2E1、 CYP2C19和CYP2C9酶均参与介导去甲斑蝥酸代谢过程。人重组CYP2E1酶介导去甲斑蝥素体外代谢呈米氏动力学过程,Km为23.64μM, CL为0.689ml/mmol CYP2E1/min;最后对体内外代谢产物进行分离鉴定,结果证实,去甲斑蝥素进入体内后,首先水解为去甲斑蝥酸,进而发生氧桥水解、六元环不同方式断裂开环或脱羧,进一步发生氧化代谢,转化为小分子化合物排出体外,或与葡萄糖醛酸、甘氨酸、谷胱甘肽等发生结合反应,增加水溶性,利用消除,软件预测与体内、体外代谢实验结果基本一致。
CYP2E1酶活性区域小,有利于小分子化合物进入,但分子内作用力和分子间范德华力能量较高,易导致酶-药物复合物不稳定；CYP2E1酶介导内外源性化合物代谢时发生变构,易导致氧化应激,诱导肝损伤发生。环孢素诱导肝损伤发病率约为30%,但其机制尚不清楚。本研究对322名长期服用环孢素进行抗排异或免疫抑制相关治疗的患者全血样本进行了CYP2E1基因型检测,首先对200名患者进行13种SNPs检测,经Hardy-Weinberg平衡检验和遗传连锁分析,从中选择6个标签SNPs,其余患者仅进行标签SNP测定,采用病例-对照研究方法,对全部患者6种标签SNPs与环孢素诱导肝损伤进行关联分析,结果显示,患者服用环孢素后,环孢素血清谷浓度与肝损伤发生未呈现明显相关性；rs3813866(-1563T>A)为环孢素诱导肝损伤易感基因(OR:2.325,95%CI:1.491-3.626).
进一步从细胞分子水平,采用点突变技术,构建rs3813866突变体质粒载体,转染至HepG-2细胞,探索易感SNP如何调控CYP2E1蛋白表达或酶活性,结果显示,rs381366突变可使CYP2E1启动子活性增强约2.46倍,mRNA水平上调约1.64倍,导致携带rs381366突变基因的患者服用环孢素后,易发生诱导肝损伤；环孢素可使CYP2E1启动子活性增强,上调启动子活性能力与药物浓度成正比,但环孢素对CYP2E1启动子活性的上调作用远小于rs381366突变的影响：环孢素对细胞中CYP2E1mRNA表达水平的影响与启动子活性相反,环孢素干预后,野生型和突变型CYP2E1mRNA均呈现下调趋势,且随环孢素浓度增加而下调明显,20μM环孢素干预后CYP2E1野生型mRNA水平下调约2倍,突变型mRNA下降可达20倍；环孢素干预可使野生型和突变型CYP2E1蛋白表达和酶活性略微增强,环孢素浓度越高,上调蛋白表达和酶活性能力越强,20μM环孢素干预后CYP2E1蛋白表达水平提高约1.72倍,酶活性增强27.28%,环孢素上调CYP2E1酶转录表达过程是否存在其它反馈调节机制仍待进一步研究。
Cytochrome P4502E1(CYP2E1) isozyme can mediate the metabolism of endogenous and exogenous compounds, and plays important roles in the studies on pharmacology and toxicology. In order to investigate the roles of CYP2E1enzyme in drug metabolism and drug-induced liver injury, we undertook this study with norcantharidin and cyclosporine as entry points.
In this study, the MetaPrint2D software was firstly used to predict metabolism sites and possible metabolites of norcantharidin and its hydrolysis product, norcantharidin acid, mainly based on the atomic fingerprint characteristics of the compounds, data mining and statistical analysis techniques by calculating the metabolism occurrence ratio; Then norcantharidin acid was docked with CYP1A2, CYP2A6, CYP2B6, CYP3A4, CYP2D6, CYP2C9, CYP2E1and CYP2C19isozymes respectively. Five of them with the top scores were chosen to be further metabolism studied in vitro with human recombined isozymes. The result showed that CYP2E1, CYP2C19and CYP2C9enzymes are mainly involved in norcantharidin acid metabolism. The metabolic prosess of norcantharidin acid mediated by recombinant human CYP2E1enzyme can be explained by Michaelis-Menten equation, with Km of23.64μM and CL of0.689ml/mmol CYP2E1/min. The results of prediction by software, metabolic experiment in vitro and metabolites speculation in vivo all confirmed that norcantharidin is firstly hydrolysed into norcantharidin acid, followed by oxygen bridge hydrolysis, six-membered ring broken by different ways or decarboxylation. Further oxidation can transform it to smaller molecules, which is easy to be eliminated, or combined with glucuronic acid, glycine or glutathione to increase the solubility; The same results of primary metabolic processe were found in rats and in vitro experiment, and the secondary metabolism similar.
The character of rotating in CYP2E1stereo structure is necessary to make its substrates such as medium-long fatty acid entering, and also can easily make the enzyme-drug complexes unstable, then lead to oxidation stress and further induce the occurrence of liver injury. The incidence of Cyclosporine-induced liver injury is about30%, but its mechanism is still unknown. A total of322subjects who were orally taking Cyclosporine to prevent rejective reaction post organ-transplanting or to cure the autoimmune disease were recruited from Qilu hospital of Shandong University (P. R. China). All the subjects were divided into drug-induced liver injury (DILI) and control group according to the results of liver function examination,200of which were genotyped for thirteen CYP2E1SNPs, followed by Hardy-Weinberg equilibrium test, linkage disequilibrium analysis and tSNP selection in the first stage. The others were analyzed only for tSNP in the next stage. Results of tSNP genotyping from two stages were merged for statistic analysis. The results demonstrated that the SNP rs3813866(-1563T>A) showed a higher risk for developing DILI (OR:2.325,95%CI:1.491-3.626).
Further study was conducted on the level of cell molecule to explore how the susceptible SNP regulate the transcription, expression and activity of CYP2E1. The mutated plasmid vector carrying rs3813866by site mutation technology was transferred into HepG-2cell, and the promoter activity, mRNA, protein expression and enzyme activity of CYP2E1were detected and compared with those of wild-type by dual-reporter gene, real-time PCR, western blot and substrate-probe methods. Besides, the same strategy was also conducted with or without Cyclosporine treatment. The results illustrated that the promoter activity of mutated-type of CYP2E1was2.46fold of wild type, and the mRNA increased by1.64times. Slight increasing of promoter activity, protein expression (1.72folder by20μM Cyclosporine) and enzyme activity (27.28%increasing by20μM Cyclosporine) can be made by Cyclosporine, but significant decreasing of mRNA was also found. The mRNA level of wild type of CYP2E1declined about2times and that of mutate-type even slipped20times after traetment by20μM Cyclosporine.
To sum up, CYP2E1play an important role in norcantharidin metabolism. The rs3813866(-1563T>A) is susceptible SNP of Cyclosporine-induced liver injury through up-regulate the promoter activity and increasing the protein expression. Further study on the feedback regulation mechanism of CYP2E1transcriptional expression during Cyclosporine interference will be conducted.
去甲斑蝥素用于肿瘤治疗多年,但其体内代谢过程尚未完全清楚。本研究首先采用MetaPrint2D软件,根据去甲斑蝥素及其水解产物去甲斑蝥酸化学结构中原子指纹特征,基于数据挖掘和统计分析技术,通过计算原子作为代谢位点的发生率,预测去甲斑蝥素及其代谢物去甲斑蝥酸代谢位点及可能代谢产物；采用Sybyl软件分别进行CYP1A2, CYP2A6, CYP2B6, CYP3A4, CYP2D6, CYP2C9, CYP2E1和CYP2C19酶与去甲斑蝥酸对接；然后选择其中得分较高者,进行人重组CYP450酶体外代谢实验,结果显示,CYP2E1、 CYP2C19和CYP2C9酶均参与介导去甲斑蝥酸代谢过程。人重组CYP2E1酶介导去甲斑蝥素体外代谢呈米氏动力学过程,Km为23.64μM, CL为0.689ml/mmol CYP2E1/min;最后对体内外代谢产物进行分离鉴定,结果证实,去甲斑蝥素进入体内后,首先水解为去甲斑蝥酸,进而发生氧桥水解、六元环不同方式断裂开环或脱羧,进一步发生氧化代谢,转化为小分子化合物排出体外,或与葡萄糖醛酸、甘氨酸、谷胱甘肽等发生结合反应,增加水溶性,利用消除,软件预测与体内、体外代谢实验结果基本一致。
CYP2E1酶活性区域小,有利于小分子化合物进入,但分子内作用力和分子间范德华力能量较高,易导致酶-药物复合物不稳定；CYP2E1酶介导内外源性化合物代谢时发生变构,易导致氧化应激,诱导肝损伤发生。环孢素诱导肝损伤发病率约为30%,但其机制尚不清楚。本研究对322名长期服用环孢素进行抗排异或免疫抑制相关治疗的患者全血样本进行了CYP2E1基因型检测,首先对200名患者进行13种SNPs检测,经Hardy-Weinberg平衡检验和遗传连锁分析,从中选择6个标签SNPs,其余患者仅进行标签SNP测定,采用病例-对照研究方法,对全部患者6种标签SNPs与环孢素诱导肝损伤进行关联分析,结果显示,患者服用环孢素后,环孢素血清谷浓度与肝损伤发生未呈现明显相关性；rs3813866(-1563T>A)为环孢素诱导肝损伤易感基因(OR:2.325,95%CI:1.491-3.626).
进一步从细胞分子水平,采用点突变技术,构建rs3813866突变体质粒载体,转染至HepG-2细胞,探索易感SNP如何调控CYP2E1蛋白表达或酶活性,结果显示,rs381366突变可使CYP2E1启动子活性增强约2.46倍,mRNA水平上调约1.64倍,导致携带rs381366突变基因的患者服用环孢素后,易发生诱导肝损伤；环孢素可使CYP2E1启动子活性增强,上调启动子活性能力与药物浓度成正比,但环孢素对CYP2E1启动子活性的上调作用远小于rs381366突变的影响：环孢素对细胞中CYP2E1mRNA表达水平的影响与启动子活性相反,环孢素干预后,野生型和突变型CYP2E1mRNA均呈现下调趋势,且随环孢素浓度增加而下调明显,20μM环孢素干预后CYP2E1野生型mRNA水平下调约2倍,突变型mRNA下降可达20倍；环孢素干预可使野生型和突变型CYP2E1蛋白表达和酶活性略微增强,环孢素浓度越高,上调蛋白表达和酶活性能力越强,20μM环孢素干预后CYP2E1蛋白表达水平提高约1.72倍,酶活性增强27.28%,环孢素上调CYP2E1酶转录表达过程是否存在其它反馈调节机制仍待进一步研究。
Cytochrome P4502E1(CYP2E1) isozyme can mediate the metabolism of endogenous and exogenous compounds, and plays important roles in the studies on pharmacology and toxicology. In order to investigate the roles of CYP2E1enzyme in drug metabolism and drug-induced liver injury, we undertook this study with norcantharidin and cyclosporine as entry points.
In this study, the MetaPrint2D software was firstly used to predict metabolism sites and possible metabolites of norcantharidin and its hydrolysis product, norcantharidin acid, mainly based on the atomic fingerprint characteristics of the compounds, data mining and statistical analysis techniques by calculating the metabolism occurrence ratio; Then norcantharidin acid was docked with CYP1A2, CYP2A6, CYP2B6, CYP3A4, CYP2D6, CYP2C9, CYP2E1and CYP2C19isozymes respectively. Five of them with the top scores were chosen to be further metabolism studied in vitro with human recombined isozymes. The result showed that CYP2E1, CYP2C19and CYP2C9enzymes are mainly involved in norcantharidin acid metabolism. The metabolic prosess of norcantharidin acid mediated by recombinant human CYP2E1enzyme can be explained by Michaelis-Menten equation, with Km of23.64μM and CL of0.689ml/mmol CYP2E1/min. The results of prediction by software, metabolic experiment in vitro and metabolites speculation in vivo all confirmed that norcantharidin is firstly hydrolysed into norcantharidin acid, followed by oxygen bridge hydrolysis, six-membered ring broken by different ways or decarboxylation. Further oxidation can transform it to smaller molecules, which is easy to be eliminated, or combined with glucuronic acid, glycine or glutathione to increase the solubility; The same results of primary metabolic processe were found in rats and in vitro experiment, and the secondary metabolism similar.
The character of rotating in CYP2E1stereo structure is necessary to make its substrates such as medium-long fatty acid entering, and also can easily make the enzyme-drug complexes unstable, then lead to oxidation stress and further induce the occurrence of liver injury. The incidence of Cyclosporine-induced liver injury is about30%, but its mechanism is still unknown. A total of322subjects who were orally taking Cyclosporine to prevent rejective reaction post organ-transplanting or to cure the autoimmune disease were recruited from Qilu hospital of Shandong University (P. R. China). All the subjects were divided into drug-induced liver injury (DILI) and control group according to the results of liver function examination,200of which were genotyped for thirteen CYP2E1SNPs, followed by Hardy-Weinberg equilibrium test, linkage disequilibrium analysis and tSNP selection in the first stage. The others were analyzed only for tSNP in the next stage. Results of tSNP genotyping from two stages were merged for statistic analysis. The results demonstrated that the SNP rs3813866(-1563T>A) showed a higher risk for developing DILI (OR:2.325,95%CI:1.491-3.626).
Further study was conducted on the level of cell molecule to explore how the susceptible SNP regulate the transcription, expression and activity of CYP2E1. The mutated plasmid vector carrying rs3813866by site mutation technology was transferred into HepG-2cell, and the promoter activity, mRNA, protein expression and enzyme activity of CYP2E1were detected and compared with those of wild-type by dual-reporter gene, real-time PCR, western blot and substrate-probe methods. Besides, the same strategy was also conducted with or without Cyclosporine treatment. The results illustrated that the promoter activity of mutated-type of CYP2E1was2.46fold of wild type, and the mRNA increased by1.64times. Slight increasing of promoter activity, protein expression (1.72folder by20μM Cyclosporine) and enzyme activity (27.28%increasing by20μM Cyclosporine) can be made by Cyclosporine, but significant decreasing of mRNA was also found. The mRNA level of wild type of CYP2E1declined about2times and that of mutate-type even slipped20times after traetment by20μM Cyclosporine.
To sum up, CYP2E1play an important role in norcantharidin metabolism. The rs3813866(-1563T>A) is susceptible SNP of Cyclosporine-induced liver injury through up-regulate the promoter activity and increasing the protein expression. Further study on the feedback regulation mechanism of CYP2E1transcriptional expression during Cyclosporine interference will be conducted.
引文
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