CN112067704A - Detection device capable of being mutually dissolved with amino acid and carnitine in human blood quantitatively and free of side effect - Google Patents
Detection device capable of being mutually dissolved with amino acid and carnitine in human blood quantitatively and free of side effect Download PDFInfo
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- CN112067704A CN112067704A CN201910442571.3A CN201910442571A CN112067704A CN 112067704 A CN112067704 A CN 112067704A CN 201910442571 A CN201910442571 A CN 201910442571A CN 112067704 A CN112067704 A CN 112067704A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/045—Standards internal
Abstract
The invention relates to a detection device capable of mutually dissolving and avoiding side effects with amino acids and carnitine in human blood quantitatively, which comprises: the kit is provided with a plurality of container holes, and an amino acid isotope standard substance, an acyl carnitine isotope standard substance, an elution solution bottle, a derivatization solution bottle, an extraction solution bottle, a redissolution bottle and a mobile phase bottle are respectively placed in each container hole; a multi-well reaction plate comprising a plurality of reaction wells; and a backing layer disposed on top of the kit and at the bottom of the multi-well reaction plate, respectively; and instructions for use of the test device. According to the technical scheme of the invention, the side effects of mutual interference, false detection rate and the like in the detection process are avoided.
Description
Technical Field
The invention relates to the field of detection of hereditary metabolic diseases, in particular to a detection device for detecting the quantitative content of amino acid and carnitine in human blood under the condition of mutual dissolution by utilizing gas chromatography and mass spectrometry in series.
Background
Genetic metabolic diseases are diseases caused by genetic defects in biosynthesis of certain enzymes, receptors, vectors and membrane pumps which are composed of polypeptides and/or proteins and are necessary for maintaining normal metabolism of the body, namely, mutation of genes encoding such polypeptides (proteins). It includes amino acids and carnitine genetic metabolic diseases.
After the diseases are developed, the diseases are progressively aggravated, if the diseases are not identified, diagnosed, intervened and treated early, early death or lifelong disability is caused, and the most of the neurological and intellectual disabilities can seriously affect the population quality, thereby causing heavy burden to families and society. Therefore, the development of early screening of IEM and the realization of early diagnosis become the key of IEM prevention and treatment, and have important significance for avoiding and reducing the occurrence of disabled children, improving the population quality and promoting the development of national economy. Currently, the diagnosis methods of IEM mainly include bacillus subtilis inhibition test, enzyme activity determination, gas chromatography-mass spectrometry (GC-MS), monogene analysis, and the like. These diagnostic methods have limitations for IEM screening: (1) the universal flux is low, generally only one to dozens of types can be detected at one time, the annual increase of the types of diseases which can be detected by IEM cannot be met, and accurate prejudgment on hereditary metabolic diseases is required; (2) different IEMs may be tested in a variety of ways, with some diseases being tested for protein levels, others for gene levels, some for urine and others for blood. Therefore, the method is not suitable for large-scale screening of hereditary metabolic diseases, and a technology capable of detecting multiple IEM diseases in high flux is urgently needed. The development of LC-MS/MS technology has made it possible to intervene in this type of disease before it occurs. The concentration of amino acid and acyl carnitine in a sample of the neonatal filter paper dried blood is analyzed by an isotope internal standard, dozens of metabolic products can be analyzed for 1 sample within 2-3 min, and about 40 hereditary metabolic diseases (including amino acid metabolic disorders, organic acid metabolic disorders and fatty acid metabolic disorders) can be screened and diagnosed by analyzing the products, so that the detection efficiency is greatly improved.
However, although some methods for detecting amino acids and carnitine exist in the prior art, the methods often have large systematic errors (such as inaccurate volume caused by pipette deviation in a transfer process), low detection sensitivity, and difficulty in simultaneously and quantitatively detecting amino acids and carnitine.
Therefore, there is a strong need in the art for a device that can simultaneously perform quantitative detection of amino acids and acylcarnitines in human blood by mutual solubility without side effects.
Disclosure of Invention
1. Technical problem to be solved
In view of the above, the technical problems to be solved by the present invention include: 1) amino acid and carnitine in blood can be well mutually dissolved so as to be convenient for detection; 2) the dissolved amino acid and carnitine can be quickly and accurately quantitatively detected; 3) without any other side effects.
2. Technical scheme
In one aspect, the present invention provides a detection device capable of quantitatively mutually dissolving amino acids and carnitine in human blood without side effects, which comprises:
the kit is provided with a plurality of container holes, and an amino acid isotope standard substance, an acyl carnitine isotope standard substance, an elution solution bottle, a derivatization solution bottle, an extraction solution bottle, a redissolution bottle and a mobile phase bottle are respectively placed in each container hole;
a multi-well reaction plate comprising a plurality of reaction wells; and
a backing layer disposed on the top of the kit and on the bottom of the multi-well reaction plate, respectively; and
instructions for the use of the test device in the test device,
the amino acid isotope standard product is characterized by comprising one or more of the following 20 amino acids: D4-L-arginine, D1-L-citrulline, D5-DL-glutamic acid, D2-L-ornithine, D4-L-methionine, D5-L-aspartic acid, 13C-glycine, D4-aminobutyric acid, D3-L-alanine, D3-asparagine, D7-hydroxyproline, D8-lysine, D6-L-valine, C7-L-phenylalanine, D7-proline, D5-serine, D13-L-leucine, D5-tryptophan, D3-methionine, D8-phenylalanine;
the isotopic standards of acyl carnitine comprise one or more of the following 12 acyl carnitines: d2-acetyl carnitine, D3-palmitoyl carnitine, D3-butyryl carnitine, D3-caproyl carnitine, D3-octanoyl carnitine, D3-lauroyl carnitine, D5-isovaleryl carnitine, D3-myristoyl carnitine, D3-propionyl carnitine, D3-decanoyl carnitine, D3-octadecanoyl carnitine, D3-free carnitine;
the elution solution comprises component a: 5mM sodium formate + 0.05% aqueous formic acid; and component B: 0.07% formic acid acetonitrile solution;
the derivatization solution comprises isopropanol and propionyl chloride, the extraction solution comprises ethanol and water, the redissolution solution comprises butyronitrile and water, and the mobile phase comprises a mixture of propylene glycol, water and formic acid, wherein the weight ratio of propylene glycol, water and formic acid is (25-30): (25-45): (50-25).
The detection apparatus according to the preceding aspect, wherein the mixed internal standard substance is prepared as a mixed internal standard solution from the methanol solution, wherein the concentration of serine in the mixed internal standard solution is 100 μ M, and the concentration of the remaining amino acids is 50 μ M.
The detection device according to the preceding aspect, further comprising a quality control substance, wherein the quality control substance is mixed plasma of a normal person.
3. Advantageous effects
The present invention is based on the following findings: in the process of detecting amino acid and acyl carnitine, the inventor finds that in order to facilitate the dissolution of the amino acid and the acyl carnitine, the proper alcohol and acid solution is added in the dissolution process, so that various amino acids and acyl carnitine can be rapidly dissolved, and the detection process is further facilitated to be accelerated. Based on the above findings, compared with the prior art, the invention has the advantages that:
(1) according to the technical scheme of the invention, various amino acids and acyl carnitine can be rapidly dissolved mutually, so that the rapid detection is facilitated;
(2) according to the technical scheme of the invention, the required sample amount is small, and the detection precision is high;
(3) according to the technical scheme of the invention, the side effects of mutual interference, false detection rate and the like in the detection process are avoided.
Detailed Description
The technical scheme in the embodiment of the invention is clearly and completely described below; it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and all other embodiments obtained by those skilled in the art without any inventive work are within the scope of the present invention.
The invention successfully develops a high-efficiency tandem mass spectrometry through extensive and intensive research and massive screening, and the method adopts specific mass spectrometry detection conditions, not only simplifies the operation, but also can simultaneously and quantitatively detect a plurality of amino acids and acyl carnitine in one detection, and has high sensitivity and high accuracy of the detection result.
1. Detection method
As used herein, "mass spectrometry" (MS) refers to an analytical technique that identifies compounds by their mass. MS techniques generally include (1) ionizing a compound to form a charged compound; and (2) detecting the molecular weight of the charged compound and calculating the mass-to-charge ratio (m/z). The compound may be ionized and detected by any suitable means. A "mass spectrometer" generally includes an ionizer and an ion detector.
The term "electron ionization" as used herein refers to a method in which an analyte of interest in a gaseous or vapor phase interacts with a stream of electrons. The interaction of the electrons with the analyte produces analyte ions, which can then be used in mass spectrometry techniques.
The term "chemical ionization" as used herein refers to a method in which a reagent gas (e.g., ammonia) is used for electron collisions and analyte ions are formed by the interaction of the reagent gas ions with analyte molecules.
2. Experimental procedures
Devices, materials and reagents
Both the Water UPLC ultra performance liquid chromatograph and the Quattro Micro tandem mass spectrometer were purchased from Waters, Inc. in the United states. An EVX-119296 well nitrogen blower and autosampler system was purchased from Apricot Designs, usa. Constant temperature incubation shaker was obtained from PerkinElmer, germany. ALPS heat sealer and hole puncher are available from Qingdao medical instruments ltd.
Reagents and materials were purchased from cambridge isotope laboratory newborn screening amino acid isotope standard suite a and carnitine and various acyl carnitine isotope standard suite B, uk.
The amino acid isotope standard substance of the kit comprises 20 amino acids which are respectively as follows: D4-L-arginine, D1-L-citrulline, D5-DL-glutamic acid, D2-L-ornithine, D4-L-methionine, D5-L-aspartic acid, 13C-glycine, D4-aminobutyric acid, D3-L-alanine, D3-asparagine, D7-hydroxyproline, D8-lysine, D6-L-valine, C7-L-phenylalanine, D7-proline, D5-serine-, D13-L-leucine, D5-tryptophan, D3-methionine, and D8-phenylalanine.
The acylcarnitine isotope standard comprises 12 carnitines, which are respectively: d2-acetyl carnitine, D3-palmitoyl carnitine, D3-butyryl carnitine, D3-caproyl carnitine, D3-octanoyl carnitine, D3-lauroyl carnitine, D5-isovaleryl carnitine, D3-myristoyl carnitine, D3-propionyl carnitine, D3-decanoyl carnitine, D3-octadecanoyl carnitine, D3-free carnitine.
Detecting a plurality of amino acids and acyl carnitine newborn screening quality control products by the United states CDC tandem mass spectrum; the pure methanol of the liquid phase mass spectrum is CNW of Shanghai ANPEL scientific instruments company; liquid mass spectrum pure water is a PROLABO (Leuven. EC) product; formic acid 98-100% is MERCK product (Damstadt, Germany). L-glutamic acid, L-aspartic acid, glycine, L-arginine, L-proline, L-ornithine, L-methionine, L-leucine, L-alanine, L-valine, L-phenylalanine and L-tyrosine are all products of national drug group chemical reagent limited company (the chromatography experiment is qualified); the L-citrulline is a SIGMA-ALDRICH product. Nunc polystyrene PS transparent 96-well plate and Nunc acrylic acid 96-well plate, polyester sealing film aluminum foil Nunc (thermo scientific). The serial mass spectrometry is used for detecting various amino acids and acyl carnitine newborn screening quality control products, extracting solutions, conversion solutions, complex solutions, 96-hole protein filter plates and 96-hole deep-hole plates.
Typically, the method of use of the kit according to the invention essentially comprises the following steps: 1, preparing an internal standard solution; 2. preparing a detection working solution; 3. obtaining a sample; 4. extracting a sample; and 5, detecting the sample. These methods or steps of use will be described in detail below.
1. Preparing an internal standard solution: adding 1.0ml of extract into lyophilized powder vial with amino acid and carnitine and acyl carnitine internal standard, covering bottle cap, shaking, and ultrasonic treating to dissolve the powder completely. Under the condition of difficult dissolution, the mixture can be placed in an oven at 37 ℃ for 3 minutes and then continuously shaken to dissolve the mixture completely.
2. Preparing a detection working solution: placing the internal standard solution at room temperature for 20 minutes; calculating the total amount of the extract liquid required by the measurement of the sample and the control in the same day according to the dosage of 100 mu L of the extract liquid in each hole; adding the extract, the amino acid internal standard solution and the acyl carnitine internal standard solution according to the volume ratio of 108:1: 1. The working solution was allowed to stabilize for 24 hours. .
3. Obtaining a sample: for neonates, blood sampling should be done 72 hours after birth, 6 milk servings. The optimal blood sampling time is about 2 hours after lactation. Sterilizing the heels of infant with 75% alcohol, and then puncturing a triangular needle into a position 1-2cm away from the heels to take blood. For adults, sampling is performed by a fingertip blood sampling method. After blood collection, the samples were dried at room temperature for at least 5 hours and sealed after being packed in plastic bags. Then, a 3.0mm diameter punch was used to punch blood spots from the quality control blood slide and the sample blood slide, respectively, and the blood spots were placed in the corresponding wells of the upper 96-well filter plate sample plate.
4. Sample extraction: extraction was carried out with 15 vol% ethanol and 85 vol% water as extraction solution. Adding 100 mu L of extracting solution into the reaction hole of the upper 96-hole protein filter plate respectively for each QC sample and sample to be tested, sealing the protein filter plate by using a protective film to ensure good sealing, and reducing the volatilization to the minimum; placing the upper 96-hole protein filter plate and the lower sample plate on an oscillator at 30 ℃, and oscillating at 750rpm/min for 30 minutes; and (4) removing the sealing film, opening a nitrogen valve, checking whether the nitrogen allowance and the pressure are normal, and placing the plate on a positive pressure instrument to perform positive pressure for 3 min.
Optionally, the sample may be subjected to a derivatization operation prior to detection, in order to improve the accuracy of detection and further reduce the probability of false detection. Derivatization a derivatization solution containing 80 vol.% isopropanol and 20 vol.% propionyl was used, the procedure being as follows: blow-drying the U-shaped bottom microporous plate by visual inspection, adding 50uL of conversion solution into each hole, and sealing the plates with paper films; placing on an oscillator at 750rpm/min, oscillating for 30min at 60 deg.C, and reacting in dark.
Then, the completely dried 96-well plate was taken out, 100. mu.L of a reconstituted solution (85 vol% butyronitrile and 15 vol% water) was added to each well, the mixture was foot-coated with an aluminum film, and the mixture was shaken at a constant temperature set at 27 ℃ at a frequency of 750rpm/min for 20 minutes. And putting the sample into a mass spectrum autosampler tray for mass spectrum detection.
5. Sample detection: the mobile phase comprises a mixture of propylene glycol, water and formic acid in a weight ratio of 30:30: 40. Remove 80. mu.l of supernatant per well with a pipette and place sequentially into a clean 96 well plate. The 96 well plates were sealed with aluminum foil. Putting into a mass spectrum autosampler tray for mass spectrum detection, injecting 20ul of sample, and injecting speed: 0 to 0.5min is 0.15ml/min, 0.5 to 1min is 0.025ml/min, and 1 to 2min is 0.5 ml/min. Each sample was 2 min. The elution solution comprises component a: 5mM sodium formate + 0.05% aqueous formic acid and component B: 0.07% formic acid in acetonitrile was added at half an hour intervals. Electrospray positive ion mode was used with tandem mass spectrometer. The ion source temperature is 120 ℃, the dissociation temperature is 350 ℃, the spray voltage is 3.5KV, the nitrogen is 5500/h, and the cone hole gas is 50 l/h. Data was collected in a Multiple Reaction Monitoring (MRM) mode. And (3) circularly detecting ion pairs in sequence for 0.05ms by each ion pair, collecting detection signals of 0.3-1.3min time period by each sample, and superposing the signal intensity for quantification. The sample can be stored for about 12 hours for mass spectrometric detection.
The multiple reaction monitoring scan mode mass spectrum parameters were as follows:
TABLE 1-1 multiple reaction monitoring scan mode Mass Spectrometry parameters
The mass spectrometric tandem assay established according to the present invention allows the diagnosis of a variety of diseases including disorders of amino acid metabolism and disorders of acyl carnitine metabolism. Tables 1-2 show the types of diseases that can be detected and the corresponding metabolic markers.
TABLE 1-2 disease classes and corresponding metabolic markers
Fourth, quantitative analysis
The software ChemoView 3.0 version is adopted, and the concentrations of various amino acids and acyl carnitine in the detected sample are automatically calculated according to isotope internal standards, ion peak intensities of various butylated amino acids and acyl carnitine and internal standards with known concentrations and a software setting program. Through the detection of the quality control sample amino acid and acyl carnitine, the recovery rate and the precision meet the requirements of screening detection.
The invention will be further illustrated with reference to the following examples. It will be understood by those of ordinary skill in the art that these examples are provided merely to illustrate the feasibility of the present invention and the effects that can be achieved according to some examples, and are not intended to limit the scope of the present invention in any way.
Example 1
By using the device according to the foregoing embodiment, more than 28800 cases of blood samples of newborn in Zhejiang province are tested, and 12 cases of methylmalonic acidemia/propionemia, 8 cases of hyperphenylalaninemia, 4 cases of maple syrup urine disease, 6 cases of citrullinemia, and the like are detected cumulatively.
Example 2
12000 newborn blood samples in Jiangxi province are detected by using the kit in the embodiment 1. 6 infants with phenylketonuria, 3 infants with propionic acidemia and 4 infants with maple syrup urine were detected cumulatively.
Therefore, the method can accurately detect various diseases such as methylmalonic acid septicemia, hyperphenylalanine septicemia, maple syrup urine disease, propionic acidemia and the like, and has high detection rate and strong anti-interference capability.
In summary, the main advantages of the present invention include:
according to the method, isopropanol is subjected to derivatization reaction with amino acid and carnitine in a sample in the presence of propionyl chloride to generate corresponding derivatives, the molecular weight is improved, amino acid fragment ions are separated from a low-resolution background, the detection sensitivity is improved, and the detection difficulty is reduced;
the experimental conditions are easy to control, and the porous plate is adopted for treatment, so that the working efficiency is improved. Because the isotope internal standard is adopted to carry out parallel synchronous treatment with the amino acid and the carnitine to be detected in the sample, the chromatographic behavior, the ionization efficiency of the mass spectrum and the matrix effect can be completely consistent, and the system error is avoided;
the protein filter plate is used, the extracting solution flows to the bottom layer sample plate by using the positive pressure instrument, the sample extracting solution is saved for transferring by one step, and the risk of inaccurate volume caused by liquid transferring deviation of a liquid transferring machine is avoided.
The above are only preferred embodiments of the present invention; the scope of the invention is not limited thereto. Any person skilled in the art should be able to cover the technical scope of the present invention by equivalent or modified solutions and modifications within the technical scope of the present invention.
Claims (3)
1. A test device for quantitatively mutually solubilizing and avoiding side effects with amino acids and carnitine in human blood, the test device comprising:
the kit is provided with a plurality of container holes, and an amino acid isotope standard substance, an acyl carnitine isotope standard substance, an elution solution bottle, a derivatization solution bottle, an extraction solution bottle, a redissolution bottle and a mobile phase bottle are respectively placed in each container hole;
a multi-well reaction plate comprising a plurality of reaction wells; and
a backing layer disposed on the top of the kit and on the bottom of the multi-well reaction plate, respectively; and
instructions for the use of the test device in the test device,
the amino acid isotope standard product is characterized by comprising one or more of the following 20 amino acids: D4-L-arginine, D1-L-citrulline, D5-DL-glutamic acid, D2-L-ornithine, D4-L-methionine, D5-L-aspartic acid, 13C-glycine, D4-aminobutyric acid, D3-L-alanine, D3-asparagine, D7-hydroxyproline, D8-lysine, D6-L-valine, C7-L-phenylalanine, D7-proline, D5-serine, D13-L-leucine, D5-tryptophan, D3-methionine, D8-phenylalanine;
the isotopic standards of acyl carnitine comprise one or more of the following 12 acyl carnitines: d2-acetyl carnitine, D3-palmitoyl carnitine, D3-butyryl carnitine, D3-caproyl carnitine, D3-octanoyl carnitine, D3-lauroyl carnitine, D5-isovaleryl carnitine, D3-myristoyl carnitine, D3-propionyl carnitine, D3-decanoyl carnitine, D3-octadecanoyl carnitine, D3-free carnitine;
the elution solution comprises component a: 5mM sodium formate + 0.05% aqueous formic acid; and component B: 0.07% formic acid acetonitrile solution;
the derivatization solution comprises isopropanol and propionyl chloride, the extraction solution comprises ethanol and water, the redissolution solution comprises butyronitrile and water, and the mobile phase comprises a mixture of propylene glycol, water and formic acid, wherein the weight ratio of propylene glycol, water and formic acid is (25-30): (25-45): (50-25).
2. The detection device according to claim 1, wherein the mixed internal standard substance is prepared into a mixed internal standard solution by the methanol solution, wherein the concentration of serine in the mixed internal standard solution is 100 μ M, and the concentration of the rest amino acids is 50 μ M.
3. The test device of claim 1, further comprising a quality control substance, the quality control substance being a mixed plasma of a normal human.
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| US20120208282A1 (en) * | 2009-07-02 | 2012-08-16 | Biocrates Life Sciences Ag | Method For Normalization in Metabolomics Analysis Methods with Endogenous Reference Metabolites. |
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Application publication date: 20201211 |