CN102565252A - 检测血液或尿液中同型半胱氨酸含量的方法 - Google Patents
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Abstract
本发明公开了一种检测血液或尿液中同型半胱氨酸含量的方法，包括如下步骤：将标品、待测样本分别和内标溶液混匀，加入基质溶液，混匀；加入巯基乙醇、二硫苏糖醇或TCEP混匀，静置10min；加入质量百分含量10％的三氯乙酸，高速离心，取上清液，用去离子水稀释，与流动相一起流经色谱柱进入液相-质谱分析，最终测定血液或尿液中同型半胱氨酸的含量。本发明的检测同型半胱氨酸含量的方法，简便、快速、灵敏，不仅可以应用于大量样本筛查，而且定量准确、特异性强。
Description
技术领域
本发明涉及一种检测血液或尿液中同型半胱氨酸含量的方法。
背景技术
同型半胱氨酸作为独立的心血管风险指标已被广泛接受，是高血脂、吸烟、糖尿病之外的又一危险因子。同型半胱氨酸除与血管疾病有关外，还与神经管畸形、先兆子痫、帕金森病、胎儿生长缓慢、慢性肾功能衰竭等多种疾病及某些药物、肿瘤的影响有关。目前，同型半胱氨酸的定量测定主要采用酶免试剂盒方法，但酶免试剂盒方法具有时间长、价格高，准确性低，不能大规模应用等缺点。而我们建立的液相串联质谱的检测方法是一种简单、高效、灵敏且准确度高的定量测定方法，为大规模应用提供了必要条件。
发明内容
本发明的目的是提供一种特异性强、准确度和灵敏度高、分析时间短的检测血液或尿液中同型半胱氨酸含量的方法。
本发明所提供的检测血液或尿液中同型半胱氨酸含量的方法，包括如下步骤：
将标品、待测样本分别和内标溶液混匀，加入基质溶液，混匀；加入巯基乙醇、二硫苏糖醇或三(2-氯乙基)磷酸酯(TCEP)混匀，静置10min；加入质量百分含量10％的三氯乙酸，高速离心，取上清液，用去离子水稀释，与流动相一起流经色谱柱进入液相-质谱分析，最终测定血液或尿液中同型半胱氨酸的含量。
本发明的检测血液或尿液中同型半胱氨酸含量的方法，其中：所述基质溶液为质量百分含量4％的牛血清蛋白溶液、生理盐水或空白血浆溶液。
本发明的检测血液或尿液中同型半胱氨酸含量的方法，其中：所述流动相为水∶有机相＝90∶10，其中所述水相含有体积百分含量0.2％的甲酸，所述有机相中含有体积百分含量0.1％的甲酸。
本发明的检测血液或尿液中同型半胱氨酸含量的方法，其中：所述TCEP的浓度为120g/L。
本发明的检测同型半胱氨酸含量的方法以同位素为内标，使得目标化合物的识别更为准确，同时更好的消除了系统误差，定量结果更为准确。添加基质溶液，模拟体液环境，消除基质效应，提高了同型半胱氨酸的回收率。以巯基乙胺为还原试剂，可以将与蛋白质残基结合的同型半胱氨酸全部还原出来，以游离形式存在。本发明用10％的三氯乙酸除蛋白，除去蛋白的效率较高。用去离子水稀释上清液可以降低三氯乙酸的浓度，结合较小的进样量，降低离子抑制作用。本发明的检测同型半胱氨酸含量的方法，简便、快速、准确，不仅可以应用于大规模样本检测，而且定量准确。
附图说明
图1为标准品(同型半胱氨酸)的色谱图。
图2为内标品(D4-同型半胱氨酸)的色谱图。
图3为血清中同型半胱氨酸的色谱图。
图4为血清中内标(D4-同型半胱氨酸)色谱图。
图5为同型半胱氨酸质谱图。
图6为内标D4-同型半胱氨酸质谱图。
具体实施方式
步骤1：用移液器移取标品和内标溶液，涡旋仪混匀；同时平行移取待测样本和内标溶液涡旋混匀；
步骤2：向上述混合液中加入基质溶液(质量百分含量4％的牛血清蛋白溶液、生理盐水或空白血清溶液)，涡旋混匀；
步骤3：分别加入巯基乙胺、巯基乙醇、二硫苏糖醇或120g/L TCEP，充分混匀；
步骤4：静置10min；
步骤5：加入除蛋白试剂试剂(质量百分含量10％的三氯乙酸)，涡旋混匀，高速离心；
步骤6：取上清液，用去离子水稀释；
步骤7：取上清溶液，由液相自动进样器进样，经液相色谱柱的色谱分离，经质谱分析，最终定量分析血液或尿液中同型半胱氨酸的含量。
液相色谱条件：
样品经液相的自动进样器进样，流动相为水∶有机相＝90∶10，其中水相含有0.2％的甲酸，有机相中含有0.1％的甲酸，等度洗脱分离，流速200μL/min，进样量3μL。色谱柱：Discovery C18(SUPELCO，HPLC，5cm*2.1mm，5μm)
三重四级杆串联质谱仪条件：
ESI离子源，正离子扫描；MRM模式，扫描时间2.5min，喷雾电压5000V，鞘气(氮气)30psi，辅助气(氮气)10psi，毛细管温度450℃，碰撞气(氮气)1.5mTorr；m/z 136→90、m/z 136→118作为Hcy的特征定性离子对，m/z 140→94、m/z 140→122作为内标D4-Hcy的特征定性离子对，m/z 136→90用于Hcy定量，CE为15eV，扫描时间0.5s，扫描宽度1u。
四种还原试剂对测定值的影响见表1，采用巯基乙胺还原的样本，其最终产物的色谱峰强度小于其他3种还原试剂还原的样本色谱峰强度。
表1.不同还原试剂测定值结果比较
不同静置时间对测定值的影响见表2，其它条件不变的情况下，静置10min，检测结果最准确。
表2.静置时间比较
二.检测实例
步骤1：用移液器移取30μL的标品溶液(浓度10-1000μmol/l，可自行依据待测物的浓度范围配制不同浓度的标品溶液)、30μL的待测血清分别与10μL的浓度为76μmol/l的同位素内标溶液(D4-同型半胱氨酸：D4-Hcy)混合，涡旋仪混匀；
步骤2：向上述标液和内标的混合液中加入质量百分含量4％的牛血清蛋白溶液，涡旋混匀；
步骤3：再加入巯基乙醇，充分混匀；
步骤4：静置10min；
步骤5：加入除蛋白试剂试剂(质量百分含量10％的三氯乙酸)，涡旋混匀，高速离心；
步骤6：取上清液，用去离子水稀释；
步骤7：取上清溶液，由液相自动进样器进样，经液相色谱柱的色谱分离，经质谱分析，最终定量分析血清中同型半胱氨酸(Hcy)的含量。
液相色谱条件：
样品经液相的自动进样器进样，流动相为水∶甲醇＝90∶10，其中水相含有0.2％的甲酸，甲醇中含有0.1％的甲酸。，等度洗脱分离，流速200μL/min，进样量3μL。色谱柱：Discovery C18(SUPELCO，HPLC，5cm*2.1mm，5μm)
三重四级杆串联质谱仪条件：
ESI离子源，正离子扫描；MRM模式，扫描时间2.5min，喷雾电压5000V，鞘气(氮气)30psi，辅助气(氮气)10psi，毛细管温度450℃，碰撞气(氮气)1.5mTorr；m/z 136→90、m/z 136→118作为HCY的特征定性离子对，m/z 140→94、m/z 140→122作为内标D4-HCY的特征定性离子对，m/z 136→90用于HCY定量，CE为15eV，扫描时间0.5s，扫描宽度1u。
标准品(同型半胱氨酸)及其内标(D4-同型半胱氨酸)的色谱图如图1、2、5和6所示。
血清样本中同型半胱氨酸及其内标D4-同型半胱氨酸的色谱图如图3和4所示，表明该方法的特异性强、准确度和灵敏度高。
以上的实施例仅仅是对本发明的优选实施方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通工程技术人员对本发明的技术方案作出的各种变形和改进，均应落入本发明的权利要求书确定的保护范围内。
Claims (4)
1.检测血液或尿液中同型半胱氨酸含量的方法，包括如下步骤：
将标品、待测样本分别和内标溶液混匀，加入基质溶液，混匀；加入巯基乙醇、二硫苏糖醇或TCEP混匀，静置10min；加入质量百分含量10％的三氯乙酸，高速离心，取上清液，用去离子水稀释，与流动相一起流经色谱柱进入液相-质谱分析，最终测定血液或尿液中同型半胱氨酸的含量。
2.根据权利要求1所述的方法，其特征在于：所述基质溶液为质量百分含量4％的牛血清蛋白溶液、生理盐水或空白血浆溶液。
3.根据权利要求1或2所述的方法，其特征在于：所述TCEP的浓度为120g/L。
4.根据权利要求3所述的方法，其特征在于：所述流动相为水∶有机相＝90∶10，其中所述水相含有体积百分含量0.2％的甲酸，所述有机相中含有体积百分含量0.1％的甲酸。
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| CN106442836A (zh) * | 2016-10-09 | 2017-02-22 | 辽宁润生康泰生物医药科技有限公司 | 一种用于检测血浆中叶酸与含硫氨基酸含量的方法 |
| CN110441457A (zh) * | 2019-08-02 | 2019-11-12 | 深圳市绿航星际太空科技研究院 | 一种检测尿液中同型半胱氨酸的方法 |
| CN111239292A (zh) * | 2019-10-24 | 2020-06-05 | 丁芬 | 同时检测多种脂溶性维生素和同型半胱氨酸的方法 |
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