基于高分辨质谱技术的β-受体激动剂在猪体内的代谢研究
摘要
为了保障动物源食品安全,p-受体激动剂(β-AAs)类物质已经被大多数国家禁止在食品动物养殖中用作促生长剂。在我国,农业部176号公告和1519号公告等先后禁止了14种β-AAs类物质在饲料和动物饮用水中使用。然而,除克伦特罗和莱克多巴胺等几种物质外,大多数β-AAs类物质在畜禽体内的代谢和残留规律还不清楚,因此,建立相关的残留检测方法缺乏必要的科学依据。本研究将以克伦特罗、沙丁胺醇、氯丙那林和苯乙醇胺A等为代表,研究不同结构特点的β-AAs在猪体内的代谢规律,为选择残留检测标示物和建立残留分析方法提供必要参考,对有效监控养殖中β-AAs的非法使用有重要意义。
本研究首先应用电喷雾-四级杆-飞行时间质谱(ESI-Q-TOF MS),分别采集了9种β-AAs的高分辨二级质谱(MS/MS)信息,并分析了碎片离子的元素组成、可能结构和碎裂途径。同时,还用同位素标记物质对相关的断裂位点、氢重排等进行了确证。结果表明,在β-AAs类化合物的质谱裂解过程中,p-羟基首先断裂失去一分子H20,生成碎片离子[M+H-H2O]+,然后,侧链仲胺上烷基取代基断裂后,生成稳定的苯乙烯胺正离子([M+H-H2O-Alkyl]+)。另外,苯环取代基或侧链胺基也可以继续发生裂解,生成不同的碎片离子。其中,[M+H-H2O-Alkyl]+为β-AAs的特异性碎片离子。以上结果,将为基于液相色谱-串联质谱联用技术(LC-MS/MS)对β-AAs的残留分析和代谢研究提供实验依据。
按10mg/kg b.w的剂量给猪口服克伦特罗(CLE),应用UPLC-Q-TOF MS和MSE进行数据采集,综合运用MDF、PIF和EIC等数据处理技术,在给药后24h内的猪尿液中检测到了8种代谢产物,主要包括4-N-氧化代谢产物(4-N-OH-CLE和4-NO2-CLE)和葡萄糖醛酸结合产物(GLU-CLE和GLU-OH-CLE)。其中,CLE原形和4-N-OH-CLE的相对含量分别为69.9%和19.1%,GLU-CLE和GLU-OH-CLE的比例小于10%。结果表明,CLE在猪体内的主要代谢途径为苯胺的氧化,在尿液中主要以原形的形式存在。
按10mg/kgb.w的剂量给猪口服沙丁胺醇(SAL),应用UPLC-Q-TOF MS和MSE进行数据采集,综合运用MDF和EIC等数据处理技术,在给药后24h内的猪尿液中检测到了10种代谢产物,主要包括苯环羟基化代谢产物(OH-SAL)、苄醇氧化代谢产物(COOH-SAL)、甲基化产物(CH3-OH-SAL)和葡萄糖醛酸结合产物(GLU-SAL和GLU-OH-SAL)。其中,COOH-SAL和CH3-OH-SAL为未报道SAL的新代谢产物。除未代谢的SAL原形(44.3%)外,葡萄糖醛酸结合物(GLU-SAL)是含量最高的代谢物(37.8%),其次为苄醇的氧化产物(COOH-SAL,16.6%)。结果表明,SAL在猪体内的主要代谢途径为葡萄糖醛酸结合和苄醇的氧化。
按10mg/kgb.w的剂量给猪口服氯丙那林(CLO),应用UPLC-Q-TOF MS和MSE进行数据采集,综合运用MDF、PIF和EIC等数据处理技术,在给药后24h内的猪尿液中检测到了9种代谢产物,包括苯环的羟基化产物(OH-CLO)、葡萄糖醛酸结合物(GLU-CLO和GLU-OH-CLO)和硫酸结合物(SO3-CLO)。其中,CLO原形的相对含量为21.6%,GLU-OH-CLO是含量最高的代谢物(53%),明显高于GLU-CLO(17.6%)。以上结果表明,CLO在猪体内的主要代谢途径为苯环的羟基化及其随后的葡萄糖醛酸结合。
按10mg/kg b.w的剂量给猪口服苯乙醇胺A (PEAA),应用UPLC-Q-TOF MS和MSE进行数据采集,综合运用MMDF和EIC等数据处理技术,在尿液、粪便、肌肉、肝脏、肾脏和肺脏中检测到了22种代谢产物。包括脱甲基代谢产物(DM-PEAA)、苯环羟基化产物(OH-PEAA)、硝基还原产物(NH2-PEAA和DM-NH2-PEAA)及其乙酰化代谢(Ac-DM-NH2-PEAA)、不同基团的葡萄糖醛酸结合物(GLU-PEAA、GLU-DM-PEAA和GLU-OH-PEAA)和硫酸结合物(SO3-DM-PEAA)等。在尿液中,PEAA原形得比例小于1%,以Ⅱ相结合代谢为主(95%),其中,GLU-DM-PEAA的相对含量最多(大于59%),其次是GLU-PEAA(约22%),是尿液中的主要代谢产物。而在粪便中,以DM-PEAA为主(50%),其次是GLU-PEAA。在肝脏和肾脏中,也是以Ⅱ相结合代谢为主(大于85%),主要代谢产物也是GLU-DM-PEAA。在肌肉和肺脏中,Ⅱ相代谢产物的含量较低,以DM-PEAA为主。以上结果表明,PEAA在猪体内的主要代谢途径是O-脱甲基及其葡萄糖醛酸结合代谢。
在本研究中,应用UPLC-Q-TOF MS建立了猪尿液和不同组织中PEAA和DM-PEAA的定量分析方法,并从特异性、灵敏度、基质效应、线性范围和精密度等方面进行了方法学考察。利用以上UPLC-Q-TOF MS方法,分别在不酶解和酶解两种条件下,测定了停药24h后肌肉、肺脏、肝脏和肾脏组织中,以及停药后不同时间段内尿液中PEAA和DM-PEAA的浓度,同时还筛查样品中的GLU-PEAA和GLU-DM-PEAA。在不酶解和酶解的条件下,PEAA和DM-PEAA在不同组织中的浓度顺序都是：肺脏>肾脏>肝脏>肌肉,说明肺脏对PEAA和DM-PEAA有明显的蓄积作用。另外,在肌肉和肺脏中,游离态PEAA和DM-PEAA的比例大于80%,而在尿液、肝脏和肾脏中,游离态PEAA和DM-PEAA的比例小于20%。在尿液和所有组织中,DM-PEAA的浓度都大于PEAA。而且,DM-PEAA在尿液中的残留时间大于PEAA。因此,在监控PEAA非法使用时,DM-PEAA更适合作为尿液和组织中的残留检测的目标物。
β-Adrenergic agonists (P-AAs), used as bronchodilators in human and veterinary medicines, are also illegally used at high dose as growth promoters in food animal production. In view of the potential risk for consumers' health, the use of β-AAs for growth-promoting purposes has been banned in many countries. In China, fourteen β-AAs have been has been prohibited from being used in animal feed and drinking water by the Ministry of Agriculture of China. However, no information about the metabolism and residue kinetics of banned β-AAs in livestock was available, except for clebuterol and ractopamine. In this study, in vivo metabolism of clenbuterol, salbutamol, clorprenaline and phenylethanolamine A were sutudied in swine, which will provide valuable data for establishing analytical method β-AAs residues, and contribute to more effective surveillance of PEAA abuse in livestocks.
In this study, high resolution MS/MS spectras of nine β-AAs were obtained using ESI-Q-TOF MS, and element compositions and possible strutures of fragment ions were studied. Besides, fragmentaton positions and rearrangements were confirmed using deuterated analogues. Loss of H2O from P-OH group and elimination of N-alkyl were proposed as two primary fragmentation pathways of various β-AAs, corresponding to characteristics fragment ions of [M-H2O+H]+and [M+H-H2O-Alkyl]+. Informations povided in this study will be of help for method development and metabolite identicatin based on LC-MS/MS methods.
After a single dose of10mg/kg b.w clenbuterol (CLE), eight metabolites were screened and identificated in swine urine collected0-24h after administration using ultra performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF MS) with MDF, EIC and IPF processing methods. The detected metabolites included4-N-hydroxylamine-CLE(4-N-OH-CLE),4-nitro-CLE(4-NO2-CLE) and several glucuronide acid conjugates(GLU-CLE and GLU-OH-CLE). In urine collected0-24h after administration, relatieve percentages of parent CLE and4-N-OH-CLE were69.9%and19.1%, respectively, suggesting that4-N-oxidization was the major metabolic pathway of CLE in swine.
After a single dose of10mg/kg b.w salbutamol (SAL), ten metabolites were screened and identificated in swine urine collected0-24h after administration using UPLC-Q-TOF MS with MDF and EIC processing methods. The detected SAL metabolites included hydroxylated-SAL(OH-SAL), benzoic acid-SAL(COOH-SAL), methylated-SAL (CH3-OH-SAL) and several glucuronide acid conjugates (GLU-SAL and GLU-OH-SAL). Among those detcted metabolites, COOH-SAL and CH3-OH-SAL were found for the first time in animals. In urine collected0-24h after administration, relatieve percentages of parent SAL, GLU-SAL and COOH-SAL were44.3%,37.8%and16.6%, respectively, suggesting that glucuronidation and oxidation of benzyl alcohol were two major metabolic pathways of CLE in swine.
After a single dose of10mg/kg b.w clorprenaline (CLO), nine metabolites were screened and identificated in swine urine collected0-24h after administration using UPLC-Q-TOF MS with MDF, IPF and EIC processing methods. The detected SAL metabolites included hydroxylated-CLO(OH-CLO), glucuronide acid conjugates (GLU-CLO and GLU-OH-CLO) and sulphate conjugates (SO3-CLO). Among those detcted metabolites, COOH-SAL and CH3-OH-SAL were found for the first time in animals. In urine collected0-24h after administration,the relatieve percentages of GLU-OH-CLO and GLU-CLO were53%and17.6%, respectively, suggesting that hydroxylation and glucuronidation of CLO were major metabolic pathways of CLO in swine.
After a single dose of10mg/kg b.w phenylethanolamine A (PEAA), twenty-two metabolites were screened and identificated in swine urine, feces, muscle, liver, kindey and lung using UPLC-Q-TOF MS with MMDF and EIC processing methods. The primary metabolites of PEAA included demethylated-PEAA (DM-PEAA), hydroxylated-CLO (OH-PEAA), nitro reduction-PEAA (NH2-PEAA) and glucuronide acid conjugates (GLU-PEAA). Besides, glucuronide acid conjugates, sulphate conjugates and acetylatied products of its primary metabolites were also found in urine and various tissues. In urine, liver and kindey, phase II metabolites were more abundant, and GLU-DM-PEAA was the major metabolite PEAA. In feces, muscle and lung, DM-PEAA was the dominant metabolites. The result suggested that O-demethylation and glucuronidation were major metabolic pathways of PEAA in swine.
In this study, quantitative analysis method for PEAA and DM-PEAA was developed using UPLC-Q-TOF MS in urine and various tissues, which were carefully validated in terms of specificity, sensitivity, linear ranges, accuracy and precision. With the validated UPLC-Q-TOF MS method, concentrations of PEAA and DM-PEAA in urine and various tissues after administration were determined without and with enzyme hydrolysis. The result showed that lung had the highest concentrations of PEAA and DM-PEAA of all tissues, indicating the potential accumutation effect on PEAA. In muscle and lung, the free PEAA and DM-PEAA were dominant forms. On the contrary, the conjugates were the primary forms of PEAA and DM-PEAA. Besides, DM-PEAA and its conjugates showed higher residual concentrations in swine, and were eliminated more slowly than than those of parent PEAA in urine. According to the results, DM-PEAA might be more appropriate potential marker in swine urine and tissues for monitoring the illicit use of PEAA.
本研究首先应用电喷雾-四级杆-飞行时间质谱(ESI-Q-TOF MS),分别采集了9种β-AAs的高分辨二级质谱(MS/MS)信息,并分析了碎片离子的元素组成、可能结构和碎裂途径。同时,还用同位素标记物质对相关的断裂位点、氢重排等进行了确证。结果表明,在β-AAs类化合物的质谱裂解过程中,p-羟基首先断裂失去一分子H20,生成碎片离子[M+H-H2O]+,然后,侧链仲胺上烷基取代基断裂后,生成稳定的苯乙烯胺正离子([M+H-H2O-Alkyl]+)。另外,苯环取代基或侧链胺基也可以继续发生裂解,生成不同的碎片离子。其中,[M+H-H2O-Alkyl]+为β-AAs的特异性碎片离子。以上结果,将为基于液相色谱-串联质谱联用技术(LC-MS/MS)对β-AAs的残留分析和代谢研究提供实验依据。
按10mg/kg b.w的剂量给猪口服克伦特罗(CLE),应用UPLC-Q-TOF MS和MSE进行数据采集,综合运用MDF、PIF和EIC等数据处理技术,在给药后24h内的猪尿液中检测到了8种代谢产物,主要包括4-N-氧化代谢产物(4-N-OH-CLE和4-NO2-CLE)和葡萄糖醛酸结合产物(GLU-CLE和GLU-OH-CLE)。其中,CLE原形和4-N-OH-CLE的相对含量分别为69.9%和19.1%,GLU-CLE和GLU-OH-CLE的比例小于10%。结果表明,CLE在猪体内的主要代谢途径为苯胺的氧化,在尿液中主要以原形的形式存在。
按10mg/kgb.w的剂量给猪口服沙丁胺醇(SAL),应用UPLC-Q-TOF MS和MSE进行数据采集,综合运用MDF和EIC等数据处理技术,在给药后24h内的猪尿液中检测到了10种代谢产物,主要包括苯环羟基化代谢产物(OH-SAL)、苄醇氧化代谢产物(COOH-SAL)、甲基化产物(CH3-OH-SAL)和葡萄糖醛酸结合产物(GLU-SAL和GLU-OH-SAL)。其中,COOH-SAL和CH3-OH-SAL为未报道SAL的新代谢产物。除未代谢的SAL原形(44.3%)外,葡萄糖醛酸结合物(GLU-SAL)是含量最高的代谢物(37.8%),其次为苄醇的氧化产物(COOH-SAL,16.6%)。结果表明,SAL在猪体内的主要代谢途径为葡萄糖醛酸结合和苄醇的氧化。
按10mg/kgb.w的剂量给猪口服氯丙那林(CLO),应用UPLC-Q-TOF MS和MSE进行数据采集,综合运用MDF、PIF和EIC等数据处理技术,在给药后24h内的猪尿液中检测到了9种代谢产物,包括苯环的羟基化产物(OH-CLO)、葡萄糖醛酸结合物(GLU-CLO和GLU-OH-CLO)和硫酸结合物(SO3-CLO)。其中,CLO原形的相对含量为21.6%,GLU-OH-CLO是含量最高的代谢物(53%),明显高于GLU-CLO(17.6%)。以上结果表明,CLO在猪体内的主要代谢途径为苯环的羟基化及其随后的葡萄糖醛酸结合。
按10mg/kg b.w的剂量给猪口服苯乙醇胺A (PEAA),应用UPLC-Q-TOF MS和MSE进行数据采集,综合运用MMDF和EIC等数据处理技术,在尿液、粪便、肌肉、肝脏、肾脏和肺脏中检测到了22种代谢产物。包括脱甲基代谢产物(DM-PEAA)、苯环羟基化产物(OH-PEAA)、硝基还原产物(NH2-PEAA和DM-NH2-PEAA)及其乙酰化代谢(Ac-DM-NH2-PEAA)、不同基团的葡萄糖醛酸结合物(GLU-PEAA、GLU-DM-PEAA和GLU-OH-PEAA)和硫酸结合物(SO3-DM-PEAA)等。在尿液中,PEAA原形得比例小于1%,以Ⅱ相结合代谢为主(95%),其中,GLU-DM-PEAA的相对含量最多(大于59%),其次是GLU-PEAA(约22%),是尿液中的主要代谢产物。而在粪便中,以DM-PEAA为主(50%),其次是GLU-PEAA。在肝脏和肾脏中,也是以Ⅱ相结合代谢为主(大于85%),主要代谢产物也是GLU-DM-PEAA。在肌肉和肺脏中,Ⅱ相代谢产物的含量较低,以DM-PEAA为主。以上结果表明,PEAA在猪体内的主要代谢途径是O-脱甲基及其葡萄糖醛酸结合代谢。
在本研究中,应用UPLC-Q-TOF MS建立了猪尿液和不同组织中PEAA和DM-PEAA的定量分析方法,并从特异性、灵敏度、基质效应、线性范围和精密度等方面进行了方法学考察。利用以上UPLC-Q-TOF MS方法,分别在不酶解和酶解两种条件下,测定了停药24h后肌肉、肺脏、肝脏和肾脏组织中,以及停药后不同时间段内尿液中PEAA和DM-PEAA的浓度,同时还筛查样品中的GLU-PEAA和GLU-DM-PEAA。在不酶解和酶解的条件下,PEAA和DM-PEAA在不同组织中的浓度顺序都是：肺脏>肾脏>肝脏>肌肉,说明肺脏对PEAA和DM-PEAA有明显的蓄积作用。另外,在肌肉和肺脏中,游离态PEAA和DM-PEAA的比例大于80%,而在尿液、肝脏和肾脏中,游离态PEAA和DM-PEAA的比例小于20%。在尿液和所有组织中,DM-PEAA的浓度都大于PEAA。而且,DM-PEAA在尿液中的残留时间大于PEAA。因此,在监控PEAA非法使用时,DM-PEAA更适合作为尿液和组织中的残留检测的目标物。
β-Adrenergic agonists (P-AAs), used as bronchodilators in human and veterinary medicines, are also illegally used at high dose as growth promoters in food animal production. In view of the potential risk for consumers' health, the use of β-AAs for growth-promoting purposes has been banned in many countries. In China, fourteen β-AAs have been has been prohibited from being used in animal feed and drinking water by the Ministry of Agriculture of China. However, no information about the metabolism and residue kinetics of banned β-AAs in livestock was available, except for clebuterol and ractopamine. In this study, in vivo metabolism of clenbuterol, salbutamol, clorprenaline and phenylethanolamine A were sutudied in swine, which will provide valuable data for establishing analytical method β-AAs residues, and contribute to more effective surveillance of PEAA abuse in livestocks.
In this study, high resolution MS/MS spectras of nine β-AAs were obtained using ESI-Q-TOF MS, and element compositions and possible strutures of fragment ions were studied. Besides, fragmentaton positions and rearrangements were confirmed using deuterated analogues. Loss of H2O from P-OH group and elimination of N-alkyl were proposed as two primary fragmentation pathways of various β-AAs, corresponding to characteristics fragment ions of [M-H2O+H]+and [M+H-H2O-Alkyl]+. Informations povided in this study will be of help for method development and metabolite identicatin based on LC-MS/MS methods.
After a single dose of10mg/kg b.w clenbuterol (CLE), eight metabolites were screened and identificated in swine urine collected0-24h after administration using ultra performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF MS) with MDF, EIC and IPF processing methods. The detected metabolites included4-N-hydroxylamine-CLE(4-N-OH-CLE),4-nitro-CLE(4-NO2-CLE) and several glucuronide acid conjugates(GLU-CLE and GLU-OH-CLE). In urine collected0-24h after administration, relatieve percentages of parent CLE and4-N-OH-CLE were69.9%and19.1%, respectively, suggesting that4-N-oxidization was the major metabolic pathway of CLE in swine.
After a single dose of10mg/kg b.w salbutamol (SAL), ten metabolites were screened and identificated in swine urine collected0-24h after administration using UPLC-Q-TOF MS with MDF and EIC processing methods. The detected SAL metabolites included hydroxylated-SAL(OH-SAL), benzoic acid-SAL(COOH-SAL), methylated-SAL (CH3-OH-SAL) and several glucuronide acid conjugates (GLU-SAL and GLU-OH-SAL). Among those detcted metabolites, COOH-SAL and CH3-OH-SAL were found for the first time in animals. In urine collected0-24h after administration, relatieve percentages of parent SAL, GLU-SAL and COOH-SAL were44.3%,37.8%and16.6%, respectively, suggesting that glucuronidation and oxidation of benzyl alcohol were two major metabolic pathways of CLE in swine.
After a single dose of10mg/kg b.w clorprenaline (CLO), nine metabolites were screened and identificated in swine urine collected0-24h after administration using UPLC-Q-TOF MS with MDF, IPF and EIC processing methods. The detected SAL metabolites included hydroxylated-CLO(OH-CLO), glucuronide acid conjugates (GLU-CLO and GLU-OH-CLO) and sulphate conjugates (SO3-CLO). Among those detcted metabolites, COOH-SAL and CH3-OH-SAL were found for the first time in animals. In urine collected0-24h after administration,the relatieve percentages of GLU-OH-CLO and GLU-CLO were53%and17.6%, respectively, suggesting that hydroxylation and glucuronidation of CLO were major metabolic pathways of CLO in swine.
After a single dose of10mg/kg b.w phenylethanolamine A (PEAA), twenty-two metabolites were screened and identificated in swine urine, feces, muscle, liver, kindey and lung using UPLC-Q-TOF MS with MMDF and EIC processing methods. The primary metabolites of PEAA included demethylated-PEAA (DM-PEAA), hydroxylated-CLO (OH-PEAA), nitro reduction-PEAA (NH2-PEAA) and glucuronide acid conjugates (GLU-PEAA). Besides, glucuronide acid conjugates, sulphate conjugates and acetylatied products of its primary metabolites were also found in urine and various tissues. In urine, liver and kindey, phase II metabolites were more abundant, and GLU-DM-PEAA was the major metabolite PEAA. In feces, muscle and lung, DM-PEAA was the dominant metabolites. The result suggested that O-demethylation and glucuronidation were major metabolic pathways of PEAA in swine.
In this study, quantitative analysis method for PEAA and DM-PEAA was developed using UPLC-Q-TOF MS in urine and various tissues, which were carefully validated in terms of specificity, sensitivity, linear ranges, accuracy and precision. With the validated UPLC-Q-TOF MS method, concentrations of PEAA and DM-PEAA in urine and various tissues after administration were determined without and with enzyme hydrolysis. The result showed that lung had the highest concentrations of PEAA and DM-PEAA of all tissues, indicating the potential accumutation effect on PEAA. In muscle and lung, the free PEAA and DM-PEAA were dominant forms. On the contrary, the conjugates were the primary forms of PEAA and DM-PEAA. Besides, DM-PEAA and its conjugates showed higher residual concentrations in swine, and were eliminated more slowly than than those of parent PEAA in urine. According to the results, DM-PEAA might be more appropriate potential marker in swine urine and tissues for monitoring the illicit use of PEAA.
引文
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