大鼠血清尿酸液相色谱-紫外检测新方法的建立及比较研究

doi:10.12300/j.issn.1674-5817.2022.189

实验动物与比较医学 ›› 2023, Vol. 43 ›› Issue (3): 314-322.DOI: 10.12300/j.issn.1674-5817.2022.189

大鼠血清尿酸液相色谱-紫外检测新方法的建立及比较研究

夏子茵¹()(), 柴媛媛¹, 徐云霞¹, 俞沁玮¹, 黄鑫¹, 张陆勇¹^,²()(), 江振洲¹()()

^1.中国药科大学新药筛选中心, 江苏省药效研究与评价服务中心, 多靶标天然药物全国重点实验室, 南京 210009
^2.广东药科大学新药研发中心, 广州 510006

收稿日期:2022-12-14 修回日期:2023-04-13 出版日期:2023-06-25 发布日期:2023-07-18
通讯作者: 张陆勇（1962—），男，博士，教授，研究方向：新药筛选及早期成药性评价和分子毒理学。E-mail：lyzhang@cpu.edu.cn。ORCID：0000-0003-1164-7371；
江振洲（1976—），男，博士，研究员，研究方向：药源性肝脏毒性及其分子机制、代谢动力学物质基础研究。E-mail：beaglejiang@cpu.
作者简介:夏子茵（1997—），女，硕士，研究方向：药代与靶向代谢组学。E-mail：xiaziyin0701@163.com。ORCID： 0000-0003-0660-5214

Quantification of Uric Acid of Rat Serum by Liquid Chromatography-ultraviolet Detection and Its Comparison Study

Ziyin XIA¹()(), Yuanyuan CHAI¹, Yunxia XU¹, Qinwei YU¹, Xin HUANG¹, Luyong ZHANG¹^,²()(), Zhenzhou JIANG¹()()

^1.New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
^2.Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China

Received:2022-12-14 Revised:2023-04-13 Published:2023-06-25 Online:2023-07-18
Contact: ZHANG Luyong (ORCID: 0000-0003-1164-7371), E-mail: lyzhang@cpu.edu.cn;
JIANG Zhenzhou (ORCID: 0000-0002-0420-0822), E-mail: beaglejiang@cpu.edu.cn;

摘要/Abstract

摘要：

目的建立更准确、灵敏的液相色谱紫外（liquid chromatography-ultraviolet，LC-UV）检测大鼠血清尿酸的方法，并将该方法与市售试剂盒的检测结果进行比较，为氧嗪酸钾诱导的大鼠高尿酸血症模型中血清尿酸含量的准确测定提供新方法。方法采用向SPF级雄性SD大鼠腹腔注射氧嗪酸钾（300 mg/kg）的方法建立高尿酸血症大鼠模型，对照组给予等量的0.5%羧甲基纤维素钠溶液。经眼眶后静脉丛采血，离心获得大鼠血清样品，经0.1%三氟乙酸-乙腈（含内标3，4-二羟基苄胺氢溴酸盐）沉淀后，取上清液进样分析。采用Waters XBridge HILIC色谱柱（150 mm×4.6 mm，3.5 μm）对尿酸进行分离，使用乙腈（含0.5%甲酸与2 mmol/L甲酸铵）作为有机相，甲醇溶液（甲醇∶水=1∶1，含0.5%甲酸与2 mmol/L甲酸铵）作为水相，进行等度洗脱，于290 nm波长处进行检测。使用活性炭处理的血清样品作为空白生物基质，用于方法学验证。分别使用所建立的LC-UV方法与两种市售试剂盒（尿酸酶法和磷钨酸法）检测高尿酸血症模型大鼠的血清尿酸水平，并对3种检测方法的准确度进行比较。结果大鼠血清中的尿酸在10～200 μg/mL质量浓度内线性关系良好（R >0.999），定量下限为10 μg/mL，准确度为－2.17%～2.21%，批内精密度为0.52%～1.95%，批间精密度为3.04%～4.90%，提取回收率为83.12%～89.91%。在氧嗪酸钾诱导的大鼠高尿酸血症模型中，市售的磷钨酸法试剂盒测定结果显著高于LC-UV法测定结果，市售的尿酸酶法试剂盒测定结果显著低于LC-UV法测定结果，但LC-UV方法的加样回收率结果最佳（95.90%～99.96%）。结论所建立的LC-UV方法能够准确测定大鼠血清中尿酸含量，与市售试剂盒相比具有更高的准确度，推荐作为氧嗪酸钾诱导的大鼠高尿酸血症模型中血清尿酸含量的检测方法。

关键词: 尿酸, 液相色谱, 内标法, 高尿酸血症, 大鼠

Abstract:

Objective To establish a more accurate and sensitive liquid chromatography-ultraviolet (LC-UV) method for the determination of uric acid in rat serum, and compare the results with those of commercial kits, providing a new method for the accurate determination of uric acid in the rat hyperuricemia model induced by potassium oxonate. Methods A hyperuricemia model was established by intraperitoneal injection of potassium oxonate (300 mg/kg) into SPF-grade male SD rats, and the control group was administered an equal amount of 0.5% sodium carboxymethylcellulose solution. Blood samples were collected from the posterior orbital venous plexus and centrifuged to obtain serum samples. After precipitation with 0.1% trifluoroacetic acid-acetonitrile (containing the internal standard 3,4-dihydroxybenzylamine hydrobromide), the supernatant was injected for analysis. Uric acid was separated on a Waters XBridge HILIC column (150 mm×4.6 mm, 3.5 μm) using acetonitrile (containing 0.5% formic acid and 2 mmol/mL ammonium formate) as the organic phase and methanol solution (methanol∶water=1∶1, containing 0.5% formic acid with 2 mmol/L ammonium formate) as the aqueous phase for isocratic elution and detection at 290 nm. Serum samples treated with activated carbon were used as substitute matrices for the methodological verification. Serum uric acid levels in rats with potassium oxonate-induced hyperuricemia were measured using the established LC-UV method and commercially available kits (uricase and phosphotungstic acid methods), and the accuracies of the three methods were compared. Results Serum uric acid showed a good linear relationship (R>0.999) at mass concentration of 10–200 μg/mL in rats, the lower limit of quantification was 10 μg/mL, the accuracy ranged from -2.17% to 2.21%, the intra-batch precision ranged from 0.52% to 1.95%, the inter-batch precision ranged from 3.04% to 4.90%, and the extraction recovery ranged from 83.12% to 89.91%. In the rat model, the results obtained using the commercially available phosphotungstic acid method kit were significantly higher than those of the LC-UV method, and those obtained using the commercially available uricase method kit were significantly lower than those of the LC-UV method, but the LC-UV method showed the best recovery of the spiked sample (95.90%–99.96%). Conclusion The LC-UV method developed in this study can determine the concentration of uric acid in rat serum with higher accuracy than commercially available kits and is recommended for the determination of serum uric acid in the rat model of hyperuricemia induced by potassium oxonate.

Key words: Uric acid, Liquid chromatography, Internal standard method, Hyperuricemia, Rats

中图分类号:

R-332

夏子茵, 柴媛媛, 徐云霞, 俞沁玮, 黄鑫, 张陆勇, 江振洲. 大鼠血清尿酸液相色谱-紫外检测新方法的建立及比较研究[J]. 实验动物与比较医学, 2023, 43(3): 314-322.

Ziyin XIA, Yuanyuan CHAI, Yunxia XU, Qinwei YU, Xin HUANG, Luyong ZHANG, Zhenzhou JIANG. Quantification of Uric Acid of Rat Serum by Liquid Chromatography-ultraviolet Detection and Its Comparison Study[J]. Laboratory Animal and Comparative Medicine, 2023, 43(3): 314-322.

图/表 7

图1 尿酸专属性验证的色谱图注：A，10 μg/mL尿酸对照品溶液；B，50 μg/mL 3，4-二羟基苄胺氢溴酸盐（DHBA）对照品溶液；C，空白生物基质；D，定量下限样品；E，对照组（腹腔注射给予等量的0.5% CMC-Na溶液）大鼠血清（无内标）；F，对照组大鼠血清。

Figure 1 Chromatogram of uric acid specificity verificationNote： A， 10 μg/mL uric acid standard solution； B， 50 μg/mL DHBA （3，4-dihydroxybenzylamine hydrobromide ） standard solution； C， Blank biomatrix； D， Lower limit of quantitation sample； E， Rat serum （without internal standard） in the control group （intraperitoneal injection of an equal amount of 0.5% CMC-Na solution）； F， Rat serum in the control group.

图2 尿酸的标准曲线图

Figure 2 Standard curve of uric acid

表1 尿酸检测的批内/批间准确度、精密度、提取回收率以及稳定性

Table 1 Intra- and inter-batch accuracy and precision, extraction recovery and stability test of uric acid determination

尿酸质量浓度 ρ/(μg·mL^-1)	批内准确度和精密度 Intra-A&P/% (n = 5)		批间准确度和精密度 Inter-A&P/% (n = 15)		提取回收率 Extraction recovery/% (n =5)			稳定性 Stability (RE)/%
尿酸质量浓度 ρ/(μg·mL^-1)	RE	RSD	RE	RSD	$x ¯ ± s$	RSD		4 °C (n =5)		FTC (n = 5)	RT (n = 3)	-20 °C (n = 3)	-80 °C (n = 3)
10	-1.99	2.42	-3.67	5.07
25	-2.17	1.95	-3.68	4.90	89.91±4.55	5.06	-3.12		-2.19		-11.47	-1.09	-9.51
100	0.74	1.54	1.15	3.04	84.42±1.61	1.90	-2.48		-2.23		-6.85	-5.01	-14.51
160	2.21	0.52	-0.56	3.67	83.12±5.63	6.77	-5.46		-4.57		-8.41	-6.74	-12.76

表1 尿酸检测的批内/批间准确度、精密度、提取回收率以及稳定性

Table 1 Intra- and inter-batch accuracy and precision, extraction recovery and stability test of uric acid determination

尿酸质量浓度 ρ/(μg·mL^-1)	批内准确度和精密度 Intra-A&P/% (n = 5)		批间准确度和精密度 Inter-A&P/% (n = 15)		提取回收率 Extraction recovery/% (n =5)			稳定性 Stability (RE)/%
尿酸质量浓度 ρ/(μg·mL^-1)	RE	RSD	RE	RSD	$x ¯ ± s$	RSD		4 °C (n =5)		FTC (n = 5)	RT (n = 3)	-20 °C (n = 3)	-80 °C (n = 3)
10	-1.99	2.42	-3.67	5.07
25	-2.17	1.95	-3.68	4.90	89.91±4.55	5.06	-3.12		-2.19		-11.47	-1.09	-9.51
100	0.74	1.54	1.15	3.04	84.42±1.61	1.90	-2.48		-2.23		-6.85	-5.01	-14.51
160	2.21	0.52	-0.56	3.67	83.12±5.63	6.77	-5.46		-4.57		-8.41	-6.74	-12.76

图3 给药前与给药后1 h大鼠血清尿酸含量注：A，LC-UV法检测两组大鼠给药前和给药后1 h的血清尿酸浓度（CON，给予0.5%CMC-Na溶液的对照组；HUA，腹腔注射300 mg/kg氧嗪酸钾的高尿酸血症组。与CON组相比，???P<0.001；与给药前相比，###P < 0.001。n = 6）。B～C，给药前和给药后1 h三种方法测定的血清尿酸浓度比较（LC-UV，液相色谱-紫外检测法；Kit-PTA，磷钨酸法试剂盒；Kit-enzyme，尿酸酶法试剂盒。与LC-UV法相比，^P < 0.05，^^P < 0.01，^^^P<0.001。n = 6）。

Figure 3 Determination of serum uric acid concentrations in rats before and 1 h after administrationNote：（A） LC-UV method was used to detect the serum uric acid concentration of rats in the two groups before and 1 h after administration (CON, control group administered 0.5% CMC-Na solution; HUA, hyperuricemia group administered 300 mg/kg potassium oxyzate). Compared with the CON group, ???P<0.00 1; Compared to before administration, ###P<0.001. n = 6). (B-C) Serum uric acid concentration was measured using three methods before and 1 h after administration (LC-UV, liquid chromatography-ultraviolet; Kit-PTA, phosphotungstic acid method Kit; Kit-enzyme, uricase method Kit. Compared with LC-UV, ^P<0.05， ^^P<0.01， ^^^P<0.00 1. n = 6）.

表2 LC-UV法与市售试剂盒检测的加样回收率比较 (n=3, xˉ±s)

Table 2 Comparison of the spiked recovery of LC-UV method and commercially available kits

取样时间/h Time/h	加样质量浓度/(μg·mL^-1) ρ/(μg·mL^-1)	加样回收率/% Recovery of spiked samples/%
取样时间/h Time/h	加样质量浓度/(μg·mL^-1) ρ/(μg·mL^-1)	LC-UV	磷钨酸法 Kit-PTA	尿酸酶法 Kit-enzyme
0^a	10	99.97±6.86	118.83±21.22	60.05±11.2
	25	95.90±4.54	117.90±8.48	84.31±4.31
1^a	10	98.18±3.23	125.00±5.34	27.37±8.62
	25	99.64±0.99	112.96±3.85	43.55±5.38

表3 LC-UV法与磷钨酸法、尿酸酶法检测血清尿酸含量的比较

Table 3 Comparison of liquid chromatography-ultraviolet (LC-UV) method with phosphotungstic acid method and uricase method for determining serum uric acid

检测方法

Method

原理

Principle

特点

Features

局限性

Limitations

磷钨酸法

Phosphotungstic

acid method

尿酸在碱性溶液中与磷钨酸反应，生成尿囊素、二氧化碳和钨蓝，钨蓝的生成量与尿酸含量成正比

操作简单，检测时间短，成本低，可用于自动化分析

特异性差，准确度低，检测结果易受血清中其他还原性物质影响

液相色谱-紫外检测法

LC-UV

溶于流动相中的各组分经过固定相时，由于与固定相发生作用的大小不同，导致其保留时间不同

专属性强，准确度高，线性范围广，色谱柱可反复使用

成本较高、检测时间较长

尿酸酶法

Uricase method

尿酸在尿酸酶的作用下生成尿囊素、二氧化碳和过氧化氢，过氧化氢与显色剂反应显色

操作简单，检测时间短，成本低，可用于自动化分析

尿酸酶的活性易被血清中氧嗪酸钾抑制，准确度低

图4 尿酸（A）与DHBA（B）的结构式

Figure 4 Structures of uric acid （A） and 3，4-dihydroxy-benzylamine hydrobromide （DHBA）（B）

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Quantification of Uric Acid of Rat Serum by Liquid Chromatography-ultraviolet Detection and Its Comparison Study

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