CN1152964C - Process for protecting enzyme activity in serum used for quality control in clinical chemistry - Google Patents
Process for protecting enzyme activity in serum used for quality control in clinical chemistry Download PDFInfo
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- CN1152964C CN1152964C CNB011077395A CN01107739A CN1152964C CN 1152964 C CN1152964 C CN 1152964C CN B011077395 A CNB011077395 A CN B011077395A CN 01107739 A CN01107739 A CN 01107739A CN 1152964 C CN1152964 C CN 1152964C
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Abstract
The present invention relates to a method for protecting a quality control substance for medical checking, particularly to a method for protecting the activity of enzymes in quality control blood serum for clinical chemistry. The method comprises the conventional processing steps for preparing the blood serum with animal blood serum as a raw material. In the process of preparation, before liquid blood serum is refrigerated or dehydrated, trehalose is added as a stabilizing agent of blood serum enzymes; the addition quantity of the trehalose is from 0.10 to 0.25 mol measured by one liter of liquid blood serum. The quality control blood serum prepared by the method of the present invention is a multienzyme quality control product with high quality and low cost, and the quality control blood serum can completely replace import products.
Description
The present invention relates to a kind of method of protecting the medical test quality control substance, particularly relate to a kind of method of protecting enzymic activity in the serum used for quality control in clinical chemistry.
At present, each hospital of home and abroad, laboratory extensively adopt serum used for quality control in clinical chemistry to carry out quality evalution between indoor quality control and chamber, to improve clinical chemistry test result's accuracy and precision.Described quality controling serum has three kinds of liquid mixing serum, commodity freeze-dry blood serum and definite value freeze-dry blood serums, and the preparation method of liquid mixing serum is: collect that animal serum, serum are handled, low temperature is frozen; Freeze-dry blood serum is generally made basic thing with animal serum, add required composition, transfer to predetermined concentration respectively, packing final vacuum lyophilize (above content sees " medical test quality control " book that the People's Health Publisher publishes distribution in April, 1998 for details, and this book number of the edition is ISBN7-117-02852-1/R2853).Home products (as the clinical chemistry of Shanghai Biological Products Inst., Ministry of Public Health and Ministry of Health's reagent for clinical diagnosis experimental center co-production with definite value freeze-drying quality controling serum) can be used as more than ten kind of routine clinical Chemical Analysis project (as potassium, sodium, chlorine, phosphorus, calcium, blood urea nitrogen, uric acid, glucose, creatinine, total protein, albumin etc.) quality control material, but can not be as seroenzyme (as gpt, glutamic-oxal(o)acetic transaminase etc.) quality control material, reason is in the home products it is to adopt short metal ion stable period, sulfhydryl compound is made the stablizer of enzyme, so cause the active low of seroenzyme, the half life of enzyme molecule, is short, can't carry out quality control to seroenzyme; And external product (the definite value freeze-drying quality controling serum of producing as Britain RANDOX company) can be used as the quality control material of above-mentioned routine clinical Chemical Analysis project and seroenzyme, but costs an arm and a leg, and all brings economically burden for hospital and patient.
The object of the present invention is to provide a kind of method of protecting enzymic activity in the serum used for quality control in clinical chemistry, the quality controling serum that adopts the inventive method to prepare also can be used as the quality control material of seroenzyme, and price is lower.
The present invention includes with the animal serum is the common process step of feedstock production serum used for quality control in clinical chemistry, in preparation process, add the stablizer of trehalose before the freezing or dehydration of liquid serum as seroenzyme, by every liter of liquid serum, the add-on of trehalose is 0.10-0.25mol.
The product of the commercially available Shanghai of trehalose reagent two factories.
Trehalose is a kind of irreducibility disaccharide of safety non-toxic, chemistry 1-O-D-glucosido-α-1-D-glucosidose by name, and fusing point is 97 ℃, and soluble in water, hot ethanol is insoluble to ether, and molecular formula is C
12H
22O
11, relative molecular weight was 378.33 (containing two molecular crystal water), and molecular conformation formula and Haworth formula can be referring to " functional fermented product " books of China Light Industry Press's publication and distribution in 2000, and number of the edition is ISBN7-5019-2694-8/TS1644.
In order to understand essence of the present invention better, will to the protection test of seroenzyme in the freeze-dry blood serum (is example with gpt, glutamic-oxal(o)acetic transaminase, gamma glutamyl transpeptidase, alkaline phosphatase, serum lactic dehydrogenase, creatine phosphokinase) and result its new purposes in preparation quality control serum field be described with trehalose below.
1 material and dried frozen aquatic products preparation
1.1 material: trehalose is the product of Shanghai reagent two factories, adopts the TRACE of Shanghai Foxing Changzheng medical science Co., Ltd product as gpt (ALT), glutamic-oxal(o)acetic transaminase (AST), gamma glutamyl transpeptidase (the mensuration reagent of γ-GT), alkaline phosphatase (ALP), serum lactic dehydrogenase (LDH), creatine phosphokinase (CK).
1.2 contrast freeze-drying quality control product: the definite value freeze-drying quality controling serum that adopts Britain RANDOX company to produce places cold compartment of refrigerator (4-6 ℃) standby.
1.3 instrument: freeze drier, automatic clinical chemistry analyzer, BC-151 refrigerator.
1.4 the packing of serum: collect the some milliliters of PHS, detect the unit of activity of enzyme in the fresh mix serum immediately, packing then, every bottle of packing 2.0ml is in Brown Glass Brown glass bottles and jars only, not with trehalose protection (sugar-free group), to be drained off, freeze-drying; Quantitatively take by weighing four kinds of serum that trehalose is mixed with, the concentration of trehalose is respectively 0.1mol/L, 0.15mol/L, 0.2mol/L, 0.25mol/L, and every bottle of packing 2.0ml (contains the sugar group), to be drained off, freeze-drying in Brown Glass Brown glass bottles and jars only.
1.5 dried frozen aquatic products preparation: contain that glucemia is clear, sugar-free serum places in the freeze drier after the packing, open bottle cap-35 ℃ of quick-frozens after 30 minutes, it is continuous freezing 10 hours at-25 ℃ to cover bottle cap, at last, in 1 hour, allow temperature be raised to 25 ℃, serum is powdered, and packing is preserved standby in 4-6 ℃.
2 methods
2.1 adopt the enzyme kinetics method, measure the activity of serum dried frozen aquatic products (containing sugar group, sugar-free group) and Britain RANDOX company serum dried frozen aquatic products six kinds of enzymes after dehydration-rehydration respectively, and calculate the keep-alive rate (%) of enzyme.
2.2 the concrete mensuration of enzymic activity: respectively in the time of 30 days, 60 days, 120 days, 240 days, 360 days after dried frozen aquatic products (contain sugar group, sugar-free group) and the Britain RANDOX company dried frozen aquatic products rehydration, detect the vigor that contains enzyme in sugared dried frozen aquatic products, sugar-free dried frozen aquatic products and the RANDOX company dried frozen aquatic products respectively.Detection method adopts 37 ℃ of enzyme kinetics methods (Kinetic), dual wavelength, temperature of reaction, and enzyme activity unit is represented with u/L.2.3 enzyme keep-alive rate calculation formula
Calculate to observe the stability of dried frozen aquatic products (containing sugar group, sugar-free group) and Britain RANDOX company dried frozen aquatic products six kinds of enzymes after dehydration-rehydration by keep-alive rate formula.
3 results
3.1 contain six kinds of enzyme stabilities, ageing observation in the clear dried frozen aquatic products of glucemia, the sugar-free serum dried frozen aquatic products in 4 ℃ of preservation processes: the stability with two kinds of dried frozen aquatic productses were observed six kinds of enzymes among both at 30 days, 60 days, 120 days, 240 days, 360 days after the rehydration respectively the results are shown in Table 1.
Table 1
Preserve the keep-alive rate (%) of six kinds of enzymes in two kinds of serum
Time ALT AST γ-GT ALP LDH CK
(d) (Y) (N) (Y) (N) (Y) (N) (Y) (N) (Y) (N) (Y) (N)
30 100.0 81.3 103.8 89.2 97.1 97.1 99.1 98.2 99.2 98.5 100.0 84.7
60 100.0 68.2 100.0 88.5 98.3 96.7 98.0 98.2 98.8 96.4 100.0 85.0
120 100.0 43.8 100.0 80.1 98.5 85.3 93.8 80.4 100.0 89.8 100.0 58.0
240 93.8 31.3 96.2 65.4 94.1 74.6 93.1 60.7 100.0 88.4 93.0 58.8
360 93.8 27.7 95.8 55.4 93.7 65.0 92.9 56.8 98.9 86.3 93.3 57.5
Annotate: Y represents to add the trehalose protection, and N represents not add the trehalose protection, and d represents to preserve fate.
Contain glucemia and when preserving 360 days for 4 ℃, carry out rehydration clearly; the keep-alive rate of surveying six kinds of enzymes is 92.9%-98.9%; average keep-alive rate is 94.7%; and sugar-free serum carries out rehydration when preserving 30 days for 4 ℃; six kinds of enzyme losses 15.0%; carry out rehydration when preserving 360 days; the keep-alive rate of surveying six kinds of enzymes is lower than 90.0%; average keep-alive rate is 58.1%; with a toll of 41.9% (enzyme deactivation is more than 50.0%); wherein ALT carried out rehydration in the time of 360 days; the keep-alive rate only is 27.7%; loss of enzyme activity nearly 50.0% (the above-mentioned variation of six kinds of enzymes may to lose the structure moisture film of keeping its 26S Proteasome Structure and Function characteristic relevant with six kinds of enzyme molecules in the preservation process in the sugar-free serum; so sugar-free serum can't be used as the quality control material of seroenzyme); contain the six kind enzyme keep-alive rates of glucemia in clear and be 1.63 times of six kinds of enzyme keep-alive rates in the sugar-free serum, this shows that containing the trehalose of glucemia in clear truly has the good protection effect to six kinds of enzymes.Respectively after the rehydration, the former solution is more clear for visual inspection, the serum dried frozen aquatic products that contains sugar, sugar-free, and the latter's solution has turbid phenomenon, may be that lipid material generation fusion phenomenon is done in the serum dried frozen aquatic products rehydration process of sugar-free.
3.2 contain the relation between trehalose concentration in six kinds of enzyme keep-alive rates after the clear dried frozen aquatic products rehydration of glucemia and this dried frozen aquatic products, the results are shown in Table 2.
Table 2
Trehalose concentration contain glucemia clear in the keep-alive rate (%) of six kinds of enzymes
(mol/L) ALT AST γ-GT ALP LDH CK
0.10 100.0 100.0 100.0 100.0 100.0 100.0
0.15 100.0 100.0 100.0 100.0 100.0 100.0
0.20 100.0 100.0 100.0 93.7 99.2 100.0
0.25 100.0 92.3 100.0 82.1 93.8 95.3
Contain glucemia clear in the keep-alive rate of six kinds of enzymes between 82.1-100.0%, only find that concentration is that the trehalose of 0.25mol/L has outside the slight inhibition ALP, other concentration is to the keep-alive effect of other five kinds of enzymes better (keep-alive rate＞90%).To the keep-alive poor effect of six kinds of enzymes, and concentration has the phenomenon that suppresses the part enzymic activity during greater than 0.30mol/L when trehalose concentration is lower than 0.10mol/L, so the concentration of trehalose is the 0.15-0.20mol/L optimum.
3.3 contain the contrast of six kinds of enzyme keep-alive rates after the rehydration respectively of clear dried frozen aquatic products of glucemia and Britain RANDOX company freeze-drying quality control product, the results are shown in Table 3.
Table 3
Place the keep-alive rate (%) of six kinds of enzymes after domestic and international two kinds of dried frozen aquatic products rehydration
Time ALT AST γ-GT ALP LDH CK
(d) (H) (R) (H) (R) (H) (R) (H) (R) (H) (R) (H) (R)
1 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0
2 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0
3 100.0 90.9 93.3 100.0 100.0 100.0 100.0 100.0 91.3 91.1 91.1 92.2
Annotate: H represents to contain the serum dried frozen aquatic products of trehalose, and R represents the freeze-drying quality control product of Britain RANDOX company, and d represents the placement fate after the dried frozen aquatic products rehydration.
Contain clear dried frozen aquatic products of glucemia and RANDOX company dried frozen aquatic products respectively after the rehydration, 4 ℃ of following controlled observations 3 days, total keep-alive rate of six kinds of enzymes was respectively 95.9% and 95.4%, and difference is very little.
3.4 experiment also shows: trehalose is to other kind seroenzyme in the freeze-dry blood serum, also have the keep-alive effect to the seroenzyme in the liquid serum.
4 conclusions and reason are inquired into:
4.1 above-mentioned protection test has confirmed that trehalose has anti-freeze, resist drying, can stablize the non-specific defencive function of life entity cytolemma and protein structure; can strengthen the stability of enzyme in the serum; make enzyme keep-alive rate comparatively stable; and itself is not decomposed by enzyme, has provided the concentration range of trehalose keep-alive enzyme simultaneously.
4.2 the mechanism of action of trehalose can be explained by following two kinds of hypothesis:
4.2.1 water substitutes hypothesis, that is: the zymoprotein molecule in serum is because of drying, when losing the structure moisture film of keeping its 26S Proteasome Structure and Function characteristic, trehalose can connect with the hydrogen bond form mutually with the dehydration position of zymoprotein surface molecular, formed the moisture film of layer protecting film to replace losing, played the quid pro quo effect of organism moisture film, trehalose can also be connected with outside water molecules effectively by hydrogen bond, made and be the similar structure of the necessary water molecules of the body that earns a bare living, thereby protected the zymoprotein molecular surface, stablized the conformation of zymoprotein molecule, the zymoprotein structure is not destroyed;
4.2.2 vitreous state hypothesis, that is: the variation of salt concn and cause protein denaturation in the zymoprotein molecule cell that dehydration is followed under dry environment in the serum, when membrane structure changes, the zymoprotein molecule can be by the trend of long trehalose glass transition stable period, cause the formation of its amorphous external phase in trehalose, structurally similar to glass ice, the motion of zymoprotein molecule and reaction of degeneration are very faint in this structure, the biological halflife of enzyme molecule is prolonged, thereby stablized the conformation of zymoprotein molecule, the zymoprotein structure is not destroyed.
4.3 with animal serum, add after the trehalose general requirements that freeze-dry blood serum that processing step routinely makes meets the medical test quality control substance, its technical specification is:
PH：7.2-7.8(37℃)，
The lyophilized products water content:＜1%,
Variation between bottle: enzyme CV＜2%, all the other analyte CV＜1%,
Dried frozen aquatic products validity period＞24 month (4 ℃),
The longest redissolution time≤30 minute, 2-8 ℃ of steady time 〉=72 hour,
Bacterium＜100cfu/ml
Nitrogen content＜50 μ mol/L
Absorbance detects: 340nm＜4.0,460nm＜5.0,550nm＜0.9,700nm＜0.8.
From above protection test and result, can draw and the invention has the advantages that:
(1), in protection test, set up sugar-free serum dried frozen aquatic products, contain the clear dried frozen aquatic products of glucemia, Britain RANDOX company freeze-drying quality control product is that control group carries out random test; and learn result by statistics; the former two is significance or utmost point significant difference; there is the sugar group obviously to be better than the sugar-free group; the latter two differences are very little, prove that trehalose has significant keep-alive effect to the seroenzyme in the serum.
(2), the present invention's protection abundant, that inexpensive trehalose is used for the serum used for quality control in clinical chemistry enzymic activity of will originating, trehalose has been excavated new medical use, opened up a new Application Areas.The quality controling serum that the adding trehalose is made can be used as the quality control substance of seroenzyme (as gpt, glutamic-oxal(o)acetic transaminase etc.), result of use is good in the quality control of seroenzyme assay, be a kind of inexpensive multienzyme quality control product, can substitute the import quality control product fully.
The several embodiment of various details, but content of the present invention is not limited to this fully.
Embodiment 1
Get 1L health pig serum, 0.10mol trehalose and mix, place the magnetic stirrer mixing, packing, seal the back mark date, it is frozen to put low temperature below-20 ℃, makes liquid mixing serum.This example is the method for protection clinical chemistry with enzymic activity in the liquid mass control serum.
Face with preceding and take out from refrigerator, mixing gently after melting at room temperature, room temperature to be returned to, validity period are 24 months.Can be used as the indoor Quality Control thing of seroenzyme, conventional top order (as potassium, sodium, chlorine, calcium, phosphorus, glucose, cholesterol, triglyceride level, total protein, albumin, creatinine, blood urea nitrogen, uric acid etc.), also can be used for quality evalution work between chamber among a small circle (embodiment 2, embodiment 3 are herewith).
Embodiment 2
Get 1L health pig serum, 0.15mol trehalose and mix, place the magnetic stirrer mixing, packing, seal the back mark date, it is frozen to put low temperature below-20 ℃, makes liquid mixing serum.This example is the method for protection clinical chemistry with enzymic activity in the liquid mass control serum.
Embodiment 3
Get 1L health pig serum, 0.20mol trehalose and mix, place the magnetic stirrer mixing, packing, seal the back mark date, it is frozen to put low temperature below-20 ℃, makes liquid mixing serum.This example is the method for protection clinical chemistry with enzymic activity in the liquid mass control serum.
Embodiment 4
Get 1L human serum, the mixing of 0.10mol trehalose, place the magnetic stirrer mixing, be placed in after packing in the freeze drier,-35 ℃, bottle cap opened condition precooling 30 minutes, it is freezing 8.5 hours at-25 ℃ to cover bottle stopper, in 1 hour, allow built-in temperature rise to 25 ℃, the mark date, make freeze-dry blood serum.This example is the method for protection clinical chemistry with enzymic activity in the freeze-drying quality controling serum.
This freeze-dry blood serum places 4-6 ℃ of cold compartment of refrigerator, and validity period is 24 months, faces with preceding and takes out from refrigerator, mixing, at room temperature balance gently after redissolving at room temperature.Can be used as the indoor Quality Control thing of seroenzyme, conventional top order (as potassium, sodium, chlorine, calcium, phosphorus, glucose, cholesterol, triglyceride level, total protein, albumin, creatinine, blood urea nitrogen, uric acid etc.), also can be used for quality evalution work between the chamber (embodiment 5, embodiment 6 are herewith).
Embodiment 5
Get 1L human serum, the mixing of 0.15mol trehalose, place the magnetic stirrer mixing, be placed in after packing in the freeze drier,-35 ℃, bottle cap opened condition precooling 30 minutes, it is freezing 8.5 hours at-25 ℃ to cover bottle stopper, in 1 hour, allow built-in temperature rise to 25 ℃, the mark date, make freeze-dry blood serum.This example is the method for protection clinical chemistry with enzymic activity in the freeze-drying quality controling serum.
Embodiment 6
Get 1L human serum, the mixing of 0.20mol trehalose, place the magnetic stirrer mixing, be placed in after packing in the freeze drier,-35 ℃, bottle cap opened condition precooling 30 minutes, it is freezing 8.5 hours at-25 ℃ to cover bottle stopper, in 1 hour, allow built-in temperature rise to 25 ℃, the mark date, make freeze-dry blood serum.This example is the method for protection clinical chemistry with enzymic activity in the freeze-drying quality controling serum.
Claims (1)
1, the method for enzymic activity in the protection serum used for quality control in clinical chemistry; comprise with the animal serum being the common process step of the described serum of feedstock production; it is characterized in that: in preparation process, add the stablizer of trehalose before the freezing or dehydration of liquid serum as seroenzyme; by every liter of liquid serum, the add-on of trehalose is 0.10-0.25mol.
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Families Citing this family (5)
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| CN101995476B (en) * | 2009-08-10 | 2013-07-03 | 中国医学科学院北京协和医院 | Liquid quality control serum for clinical chemical detection |
| CN101893639B (en) * | 2010-02-11 | 2013-10-30 | 上海蓝怡科技有限公司 | Method for stabilizing activity of alpha-hydroxybutyricdehydrogenaseand lactic dehydrogenase of quality-control serum |
| CN102221490B (en) * | 2010-04-16 | 2012-11-21 | 北京航天总医院 | Processing method for activity stability of enzyme in human serum |
| CN103255121B (en) * | 2013-06-08 | 2014-05-21 | 北京华宇亿康生物工程技术有限公司 | Compound stabilizer for aspartate amino transferase mitochondria isozyme |
| TWI719220B (en) * | 2017-06-13 | 2021-02-21 | 英屬維爾京群島商大利緯眾生物科技股份有限公司 | A novel method for blood serum protein activity preservation |
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