CN115508483A - 一种快速检测血清样本中甲基丙二酸的lc-ms/ms方法 - Google Patents
一种快速检测血清样本中甲基丙二酸的lc-ms/ms方法 Download PDFInfo
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Abstract
本发明涉及一种快速检测血清样本中甲基丙二酸的LC‑MS/MS方法，对样本简单处理后，采用AX色谱柱，与血清样本中的琥珀酸达到完全分离，且经过优化，MMA峰型较佳，响应较好，能够实现对血清样本中的甲基丙二酸较好的分离和绝对定量。
Description
技术领域
本申请涉及血清中代谢物质的检测，属于生物检测领域。
背景技术
甲基丙二酸(MMA)是维生素B12缺乏症的功能性生物标志物。血液样本中MMA的检测难点在于MMA本身的性质及血液样本中的干扰物。MMA本身是一种分子量较小、亲水性较强的物质，在反相色谱柱上保留较差。此外，血液样本中的琥珀酸因结构跟MMA相似，且其浓度水平显著高于MMA，对血液样本中MMA的检测造成强干扰。
代谢组学是继基因组学、转录组学、蛋白质组学之后兴起的又一新的组学研究分支，代谢组学通过测量细胞、组织和机体代谢产物的浓度变化来反映基因、蛋白质和代谢活性本身的直接关系。由于代谢组学变化是机体对基因、疾病、环境和药物等作用的最终反映，其内源性代谢产物是机体一系列生命事件的关键或终点反应，因此代谢组学可以帮助人们更好地了解生物体中各种复杂的相互作用及其本质，可用于人类疾病的诊断。高效液相色谱质谱联用法(LC-MS/MS)是代谢组学研究中应用最广泛的技术平台之一，具有高灵敏度、高通量、线性范围宽等特点。
液相色谱串联质谱(LC-MS/MS)越来越广泛应用于药物、食品、环境、法医、临床等各个领域。液相色谱串联质谱中，液相色谱负责分离待测物与干扰物，质谱负责检测。样品进样后首先在流动相的携带下进入色谱柱，经过色谱柱分离后，进入质谱进行检测。质谱根据被测物的质荷比(m/z)进行检测，被测物在离子源转换成气相离子进入质谱，在三重四级杆中一级质谱扫描特定范围离子或允许特定离子进入碰撞室，在碰撞室内分子离子碰撞裂解，形成子离子进入二级质谱，二级质谱扫描特定范围离子或允许特定离子进入检测器。LC-MS/MS具有灵敏度高，选择性强，准确性好等特点，在临床检测上适用范围远远超过放射性免疫检测和化学检测范围，是其他方法无可比拟的。目前现有技术中还并没有针对血清样本中甲基丙二酸的定量和定性检测方法，本申请的目的是为了克服上述缺陷进行的技术探索。
发明内容
为克服现有技术的缺陷，发明人开发了本发明的技术方案，具体为：
本发明提供一种检测样本中甲基丙二酸的方法；所述的方法是利用液相色谱串联质谱(LC-MS/MS)的方法检测血清样本中的甲基丙二酸；所述的方法包括：
1)血清样本中甲基丙二酸的提取；
2)设置LC-MS/MS的参数条件；
3)数据处理：根据甲基丙二酸保留时间和离子对信息，对每种物质在样本中检测到的质谱峰进行校正，样本质控分析以及获得标准曲线；
所述的方法为非诊断的方法。
在一个具体的实施例中，所述的样本提取方法为：取血清样本，按照样本：溶剂为1:2～5的体积比加入70％的甲醇，涡旋混合，低温离心，备用。
在另外一个具体的实施例中，所述的LC-MS/MS检测所用的数据采集仪器系统包括超高效液相色谱(WatersHClass)和串联质谱MS/MS(Applied Biosystems6500QuadrupoleTrap)；
在另外一个具体的实施例中其中
色谱柱：Atlantis PREMIER BEH C18 AX，1.7μm，2.1*100mm；
流动相A：超纯水(10mM乙酸铵，0.5％甲酸)；
流动相B：乙腈(0.5％甲酸)；
洗针液：50％乙腈(超声脱气10min)；
柱温：40℃；流速：0.3mL/min；进样量：5μL。
在另外一个具体的实施例中，其中LC-MS/MS的洗脱梯度：0-1.5min 100％A，1.5-5min 100％A-60％A，5-7min 60％A,7-8min 100％A。
在另外一个具体的实施例中，所述的质谱条件为：
| Ion Mode | ESI- | Curtain Gas | 20 |
| IS | -4500 | Temperatμre | 350 |
| Ion Source Gas1 | 40 | Ion Source Gas2 | 40 |
| Collision Gas | Medium | Scan type | MRM |
| Entrance Potential | 10 | Collision Cell Exit Potential | 10 |
。
在另外一个具体的实施例中，其中所述的离子对信息具体为：
| Compound | 母离子 | 子离子 | 保留时间 |
| MMA-1 | 117.0 | 73.0 | 4.73 |
| MMA-2 | 117.0 | 85.1 | 4.73 |
。
在另外一个具体的实施例中，所述的标准曲线为：
本发明的第二个方面是提供第一个方面所述的方法在检测血清中甲基丙二酸含量的应用，所述的应用为非诊断的应用。
本发明的有益效果：前处理简单快捷，样本需求量低(50μL)，未经过衍生或SPE等复杂的处理。采用AX色谱柱，可以跟血清样本中的琥珀酸达到完全分离，且经过优化，MMA峰型较佳，响应较好。反相色谱柱上血清样本中的甲基丙二酸和琥珀酸较难达到基线分离。Amide色谱柱甲基丙二酸和琥珀酸虽然能分离，但是目标物甲基丙二酸保留较差(1min以前)，影响目标物的定量准确性，本发明的方法能够实现较好的分离和绝对定量。
附图说明
图1MMA标准曲线；
图2本发明方法检测的加标血清样本中MMA和琥珀酸的分离情况；
图3常规反相色谱柱分离加标血清样本中MMA和琥珀酸的情况：无法达到完全分离；
图4本发明方法检测血液样本中MMA的检出情况。
具体实施方式
1、清样本中甲基丙二酸提取方法：
取50μL血清样本，加入150μL70％甲醇，涡旋5min，在4℃条件下，12000r/min下离心15min，离心后取上清用于上机分析。
2、仪器参数条件：
本发明中LC-MS/MS检测所用的数据采集仪器系统主要包括超高效液相色谱(WatersHClass)和串联质谱MS/MS(Applied Biosystems6500Quadrupole Trap)。
其中，超高效液相色谱条件主要包括：
色谱柱：Atlantis PREMIER BEH C18 AX，1.7μm，2.1*100mm
流动相A：超纯水(10mM乙酸铵，0.5％甲酸)；
流动相B：乙腈(0.5％甲酸)；
洗针液：50％乙腈(超声脱气10min)；
柱温：40℃；流速：0.3mL/min；进样量：5μL；
洗脱梯度：0-1.5min 100％A，1.5-5min100％A-60％A，5-7min60％A，7-8min100％A；
质谱条件如下：
| Ion Mode | ESI- | Curtain Gas | 20 |
| IS | -4500 | Temperatμre | 350 |
| Ion Source Gas1 | 40 | Ion Source Gas2 | 40 |
| Collision Gas | Medium | Scan type | MRM |
| Entrance Potential | 0 | Collision Cell Exit Potential | 10 |
本发明还提供了MMA的数据处理方法，具体如下：
利用软件Analyst 1.6.3处理质谱数据。根据MMA保留时间和离子对信息，对MMA在样本中检测到的质谱峰进行校正，以确保定性定量的准确。对所样本中MMA进行定性定量分析，每个色谱峰的峰面积(Peak Area)代表对应物质的相对含量，最终得到样本中MMA的定性和定量分析结果。
离子对信息和保留时间如下表所示：
| Compound | 母离子 | 子离子 | 保留时间 |
| MMA-1 | 117.0 | 73.0 | 4.73 |
| MMA-2 | 117.0 | 85.1 | 4.73 |
(1)样本质控分析：通过对不同质控样本质谱检测分析的总离子流图(TIC图)进行重叠展示分析，以判断MMA提取和检测的重复性。
(2)标准曲线绘制：配制不同浓度的MMA标准品溶液，获取各个浓度标准品的对应定量信号的质谱峰强度数据；以标准品浓度(ng/mL)为横坐标，质谱峰的峰面积(PeakArea)为纵坐标，绘制MMA的标准曲线。
所获得的标准曲线如下表和图1所示：
| 物质 | 线性方程 | 相关系数 |
| MMA | y＝3.82239e4 x+15527.51215 | r＝0.99983 |
(3)绝对定量：将检测到的所有样本的MMA的积分峰面积分别代入标准曲线线性方程进行计算，将计算结果进一步代入含量计算公式计算后得到实际样本中MMA的含量。
虽然本发明已以较佳实施例公开如上，但是并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明精神和范围内，都可做各种改动和修饰，以本领域技术人员结合所属领域的常规技术概括获得的均在本发明的范围之内。
Claims (8)
1.一种检测样本中甲基丙二酸的方法；所述的方法是利用液相色谱串联质谱(LC-MS/MS)的方法检测血清样本中的甲基丙二酸；所述的方法包括：
1)血清样本中甲基丙二酸的提取；
2)设置LC-MS/MS的参数条件；
3)数据处理：根据甲基丙二酸保留时间和离子对信息，对每种物质在样本中检测到的质谱峰进行校正，样本质控分析以及获得标准曲线；
所述的方法为非诊断的方法。
2.根据权利要求1所述的方法，所述的样本提取方法为：取血清样本，按照样本：溶剂为1:2～5的体积比加入70％的甲醇，涡旋混合，低温离心，备用。
3.根据权利要求1或2所述的方法，所述的LC-MS/MS检测所用的数据采集仪器系统包括超高效液相色谱(WatersHClass)和串联质谱MS/MS(Applied Biosystems6500QuadrupoleTrap)；其中
色谱柱：Atlantis PREMIER BEH C18 AX，1.7μm，2.1*100mm；
流动相A：超纯水(10mM乙酸铵，0.5％甲酸)；
流动相B：乙腈(0.5％甲酸)；
洗针液：50％乙腈(超声脱气10min)；
柱温：40℃；流速：0.3mL/min；进样量：5μL。
4.根据权利要求1所述的方法，其中LC-MS/MS的洗脱梯度：0-1.5min 100％A，1.5-5min100％A-60％A，5-7min 60％A,7-8min 100％A。
5.根据权利要求1所述的方法，所述的质谱条件为：
6.根据权利要求1所述的方法，其中所述的离子对信息具体为：
。
7.根据权利要求1所述的方法，在另外一个具体的实施例中，所述的标准曲线为：
。
8.权利要求1-7任一项所述的方法在检测血清中甲基丙二酸含量的应用，所述的应用为非诊断的应用。
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