人CYP3A4两个新非同义突变酵母表达系统的建立及其多态性在体外代谢和药物筛选中研究
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摘要
人细胞色素P450 (CYP)超家族是一类混合功能单加氧酶,主要存在于肝微粒体中,参与内源性化合物(如胆汁酸、甾体类激素、脂肪酸、前列腺素等)和外源性化合物(药物、致癌物、毒物前致突变物)的生物转化。按照CYP一级结构同源性的差异,CYPs可分成多个家族。其中CYP3A家族约占CYPs总量的30%,与其他家族相比,CYP3A酶蛋白的含量在肝微粒体中占有较高的比例且存在多种形式(例如：CYP3A4, CPY3A7, CYP3A43等)。已知CYP3A4占肝脏及肠道中CYPs总含量的50%以上,负责代谢约50%的常用临床药物,因此其重要性不容忽视。研究发现,CYP3A4个体之间酶活性具有明显的差异。很多因素造成了CYP3A4差异化的表现,包括性别、药物、内源性物质、环境化学物质等。个体间在肝脏酶表达量的差异约有40倍,在药物代谢能力方面相差也达到10倍左右。非同义单核苷酸多态性(SNPs)是造成CYP3A4个体间差异达30-85%的主要遗传因素。
目前,已公布的CYP3A4 SNPs多达几十种,与野生型酶活相比,这些SNPs造成了酶活性不同程度地提高或降低。http://www.cypalleles.ki.se上公布了CYP3A4两种新非同义突变(F176V、I223R),但是这两种突变是否影响CYP3A4酶活性至今未见报道。为了研究F176V和I223R突变是否对CYP3A4酶活性造成影响,在实验室已有CYP3A4野生型cDNA模板的基础上,利用定点突变的方法分别引入两个等位基因的突变位点,然后在内切酶Kpn I和Xho I的作用下产生带有粘性末端的插入片段,此片段与同样经过Kpn I和Xho I作用而带有粘性末端的pYES2/CT载体连接,构成的重组质粒热激转化导入大肠杆菌中。由于重组质粒带有氨苄青霉素抗性标记,因此在LB-Amp平板可筛选出重组子。Kpn I和Xho I双酶切重组质粒进行初步鉴定正确后,再经测序确认。突变引入成功的质粒,经过电转将质粒导入带有CPR (CYP氧化还原酶)基因的酵母菌株中。经过Western-blotting鉴定的重组子以半乳糖大量诱导,将收获的菌体用差速离心法制备酵母微粒体,用于酶促反应动力学以及药物药物相互作用(DDIs)的研究。实验选择的特异荧光底物DBF (Dibenzyl fluorescein)在CYP3A4的作用下去甲基化产生荧光产物。酶动力学实验中所得数据经过产物标准曲线换算,应用软件GraphPad Prismd得到动力学参数Km、Vmax和内在清除率CLint(CLint= Vmax/Km),CLint是比较突变重组酶与野生型重组酶代谢差异的标准。此外,我们选取了8大类八种药物对CYP3A4野生型和两个突变型进行了药物抑制实验。
实验结果显示,两种CYP3A4的突变重组酶均代谢DBF生成相应产物。但是其Km与野生型相比均有所增大,Vmax与野生型相比有所下降。F176V、I223R的CLint与野生型相比,分别为野生型的27%和22%。药物抑制实验结果显示,一种药物对不同重组酶的抑制程度不一,但是差异并不显著；不同药物对同种重组酶的抑制亦有不同。本研究对F176V、I223R进行了酶学及药物抑制作用初步分析,为今后的实验奠定了可靠的理论基础。
Human Cytochrome P450 (CYP) is a superfamily of heme-containing mixed-function oxygenases, which exist primarily in the lipid bio-layer of the endoplasmic reticulum of hepatocytes. It participate in metabolizing a vast array of endogenous substrate like fatty acids, steroids and vitamins as well as exogenous substrate like drugs, dietary substance and environmental pollutants. Accroding to the difference of nucleotide sequence homology, CYPs can be divided into many subfamily and CYP3A account for 30%. Compare to other subfamily, not only the expression of apoenzyme is more, but the forms of the presence are varied. CYP3A4 is the most abundant isoform of CYP in adult human liver and intestinal tract, CYP3A4 is responsible for the metabolism of about 50% of commonly clinical drugs through oxidation, peroxidation, and reduction. The variable expression of CYP3A4 is at least partially due to the factors below, including induction by drugs, endogenous compounds, and environmental chemicals, but also includes genetic factors. Several studies suggested that 30～85% of the interindividual variability in CYP3A is predominantly due to genetic factors, such as non-synonymous single nucleotide polymorphisms (SNPs).
We have already known many SNPs of CYP3A4.Some of them contribute to the alteration of CYP3A4 enzyme activity. Two novel mutations of CYP3A4 were published in http://www.cypalleles.ki.se, CYP3A4 (F176V) and CYP3A4 (I223R). But no one has researched on the affection of the two new SNPs. We introduced the mutations into the c DNA of the wild type by site-specific PCR. Then the two CYP3A4 genes were sub-cloned into a yeast expression vector pYES2/CT and were chosen by the ampicilin. Following sequencing, we transported the recombinants to the yeast strain which contained NADPH-cytochrome P-450 reductase (CPR). After that we used galactose to induce the P450 enzymes expressed in yeast.Fractions that contained recombinant 3A4 enzyme were isolated by differential centrifugation. The Km, Vmax and CLint of the enzyme were determined by the unique fluorescent substrate, dibenzylfluorescein (DBF)-O-dealkylation.
From the results we could concluded, DBF could be metabolized by the two allelic enzymes. Compared to the wildtype, Km of the mutation are increase, Vmax of the mutation are decrease, CLint of the mutation are also decreas. Our study lay the foundation for the further research.
目前,已公布的CYP3A4 SNPs多达几十种,与野生型酶活相比,这些SNPs造成了酶活性不同程度地提高或降低。http://www.cypalleles.ki.se上公布了CYP3A4两种新非同义突变(F176V、I223R),但是这两种突变是否影响CYP3A4酶活性至今未见报道。为了研究F176V和I223R突变是否对CYP3A4酶活性造成影响,在实验室已有CYP3A4野生型cDNA模板的基础上,利用定点突变的方法分别引入两个等位基因的突变位点,然后在内切酶Kpn I和Xho I的作用下产生带有粘性末端的插入片段,此片段与同样经过Kpn I和Xho I作用而带有粘性末端的pYES2/CT载体连接,构成的重组质粒热激转化导入大肠杆菌中。由于重组质粒带有氨苄青霉素抗性标记,因此在LB-Amp平板可筛选出重组子。Kpn I和Xho I双酶切重组质粒进行初步鉴定正确后,再经测序确认。突变引入成功的质粒,经过电转将质粒导入带有CPR (CYP氧化还原酶)基因的酵母菌株中。经过Western-blotting鉴定的重组子以半乳糖大量诱导,将收获的菌体用差速离心法制备酵母微粒体,用于酶促反应动力学以及药物药物相互作用(DDIs)的研究。实验选择的特异荧光底物DBF (Dibenzyl fluorescein)在CYP3A4的作用下去甲基化产生荧光产物。酶动力学实验中所得数据经过产物标准曲线换算,应用软件GraphPad Prismd得到动力学参数Km、Vmax和内在清除率CLint(CLint= Vmax/Km),CLint是比较突变重组酶与野生型重组酶代谢差异的标准。此外,我们选取了8大类八种药物对CYP3A4野生型和两个突变型进行了药物抑制实验。
实验结果显示,两种CYP3A4的突变重组酶均代谢DBF生成相应产物。但是其Km与野生型相比均有所增大,Vmax与野生型相比有所下降。F176V、I223R的CLint与野生型相比,分别为野生型的27%和22%。药物抑制实验结果显示,一种药物对不同重组酶的抑制程度不一,但是差异并不显著；不同药物对同种重组酶的抑制亦有不同。本研究对F176V、I223R进行了酶学及药物抑制作用初步分析,为今后的实验奠定了可靠的理论基础。
Human Cytochrome P450 (CYP) is a superfamily of heme-containing mixed-function oxygenases, which exist primarily in the lipid bio-layer of the endoplasmic reticulum of hepatocytes. It participate in metabolizing a vast array of endogenous substrate like fatty acids, steroids and vitamins as well as exogenous substrate like drugs, dietary substance and environmental pollutants. Accroding to the difference of nucleotide sequence homology, CYPs can be divided into many subfamily and CYP3A account for 30%. Compare to other subfamily, not only the expression of apoenzyme is more, but the forms of the presence are varied. CYP3A4 is the most abundant isoform of CYP in adult human liver and intestinal tract, CYP3A4 is responsible for the metabolism of about 50% of commonly clinical drugs through oxidation, peroxidation, and reduction. The variable expression of CYP3A4 is at least partially due to the factors below, including induction by drugs, endogenous compounds, and environmental chemicals, but also includes genetic factors. Several studies suggested that 30～85% of the interindividual variability in CYP3A is predominantly due to genetic factors, such as non-synonymous single nucleotide polymorphisms (SNPs).
We have already known many SNPs of CYP3A4.Some of them contribute to the alteration of CYP3A4 enzyme activity. Two novel mutations of CYP3A4 were published in http://www.cypalleles.ki.se, CYP3A4 (F176V) and CYP3A4 (I223R). But no one has researched on the affection of the two new SNPs. We introduced the mutations into the c DNA of the wild type by site-specific PCR. Then the two CYP3A4 genes were sub-cloned into a yeast expression vector pYES2/CT and were chosen by the ampicilin. Following sequencing, we transported the recombinants to the yeast strain which contained NADPH-cytochrome P-450 reductase (CPR). After that we used galactose to induce the P450 enzymes expressed in yeast.Fractions that contained recombinant 3A4 enzyme were isolated by differential centrifugation. The Km, Vmax and CLint of the enzyme were determined by the unique fluorescent substrate, dibenzylfluorescein (DBF)-O-dealkylation.
From the results we could concluded, DBF could be metabolized by the two allelic enzymes. Compared to the wildtype, Km of the mutation are increase, Vmax of the mutation are decrease, CLint of the mutation are also decreas. Our study lay the foundation for the further research.
引文
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