喹噁啉类定量分析方法及脱氧速率研究
|
摘要
喹噁啉类是化学合成的具有抗菌、促生长作用的动物专用药,被广泛用作猪、鸡、鱼等动物的饲料添加剂,主要包括卡巴氧、喹乙醇、喹赛多、喹烯酮和乙酰甲喹等5种药物。因毒副作用,卡巴氧和喹乙醇已被禁止或限制使用。中国相继批准了乙酰甲喹和喹烯酮的使用,并正在开发较安全的喹赛多等同类替代产品。但喹噁啉类的滥用和非法使用现象普遍,药物毒性及残留造成的潜在的食品安全危害不容忽视,开展这类药物毒性作用机制及其在饲料和动物源食品中的分析方法研究具有重大意义。喹噁啉类分析方法研究禁锢于单一基质、单组分,不同基质中多种喹噁啉类分析方法研究未见报道。喹噁啉类毒性研究也仅局限于推测其源于脱氧过程,但未见毒性与脱氧速率关系的阐述。本课题从喹噁啉类分析方法展开研究,深入探索并建立饲料中喹噁啉类和动物可食性组织中喹噁啉类残留标示物的同时分析方法,进而初步探讨喹噁啉类脱氧速率和毒性的关系,具体为以下3个研究体系内容。这些研究为这类药物的残留监控和毒性作用机制等研究提供技术支持和理论依据,对动物源食品安全评价具有指导意义和参考价值。
1.饲料中喹噁啉类药物同时分析方法研究
深入探索样品前处理和检测方法,确定最佳条件,建立猪、鸡、鱼饲料中5种喹噁啉类高效液相色谱同时分析方法。样品经甲醇-水-乙腈(35:35:30,v/v/v)溶剂超声提取,中性氧化铝固相萃取小柱净化,高效液相色谱梯度洗脱分离,380 nm紫外波长测定。不同饲料样品中,5种药物的CCα小于0.45 mg/kg,CCβ小于0.75 mg/kg;在1、5、50和200 mg/kg的添加浓度,除喹赛多(＞75%)外,其它4种药物的回收率为92.1%～104.3%,日内、日间相对标准偏差为3.0%～13%。
超声提取和固相萃取净化,可以节省样品前处理时间,避免有毒试剂的使用,减少有机试剂用量,消除饲料基质对喹噁啉类药物测定干扰。仪器测定条件选择过程中,采用流动相梯度洗脱方式,考察了流动相成分和比例对5种喹噁啉类药物同时分析的影响,选用380 nm作为紫外检测器测定波长,进一步对5种喹噁啉类药物进行筛选,对比不同溶剂对药物测定分析结果差异,确定5种喹噁啉类药物同时分离分析的高效液相色谱条件。
本方法操作简便、材料易得、环境污染小,可以广泛应用于猪、鸡、鱼等饲料中多种喹噁啉类的监测,对饲料中其它化合物的多组分分析方法研究具有参考价值。
2.动物可食性组织中喹噁啉类多残留分析方法研究
探讨样品提取、净化和测定溶剂等条件,建立猪、鸡、鱼肌肉及猪、鸡肝脏组织中喹噁啉-2-羧酸和3-甲基喹噁啉-2-羧酸的高效液相色谱多残留分析方法。动物组织样品采用偏磷酸甲醇溶液水解,乙酸乙酯提取,MAX阴离子固相萃取小柱净化,碱性甲醇溶解浓缩残渣,高效液相色谱分离,320 nm紫外波长测定。猪、鸡、鱼肌肉组织中喹噁啉-2-羧酸的CCα为0.7～1.0μg/kg,CCβ为1.3～1.7μg/kg;3-甲基喹噁啉-2-羧酸的CCα为1.2～2.6μg/kg,CCβ为2.0～4.4μg/kg。猪、鸡肝脏组织中喹噁啉-2-羧酸的CCα为2.5～2.6μg/kg,CCβ为4.3～5.6μg/kg;3-甲基喹噁啉-2-羧酸的CCα为2.1～2.4μg/kg,CC∞为4.4～5.6μg/kg。喹噁啉-2-羧酸和3一甲基喹噁啉-2-羧酸在各动物肌肉组织中添加浓度为2.0～16μg/kg,回收率为70.7%～104.3%,相对标准偏差＜20%;在猪、鸡肝脏组织添加浓度为10～50μg/kg,回收率为72.3%～80.7%,相对标准偏差＜13%。
酸性环境水解样品,结合阴离子固相萃取小柱净化,简化了样品前处理步骤,避免强酸、强碱和有毒试剂的使用,可有效消除基质对药物测定的干扰,扩大了分析样品范围,方法灵敏度高。对比不同样品溶剂对两种分析物紫外吸收的影响,明确其经样品前处理后紫外吸收波长的变化,选用碱性甲醇溶剂,抵消了分析物紫外吸光度变化值,减小了回收率测定误差,提高了分析方法的准确度。
本方法样品前处理简单、基质干扰少、分析范围广、检测灵敏度高,基本达到国际领先水平,可广泛应用于喹噁啉类药物的残留监测,对动物组织中多残留分析方法研究具有指导意义,为动物性食品安全评价提供技术支持。
3.喹噁啉类脱氧速率研究
建立脱二氧喹赛多、脱二氧喹烯酮和脱二氧喹乙醇的高效液相色谱测定方法,为喹噁啉类脱氧产物定性分析提供技术方法。3种化合物经高效液相色谱流动相梯度洗脱分离,二极管阵列检测器测定,检测限为0.01μmol/L,定量限为0.02μmol/L,在0.01～10μmol/L范围内,线性关系良好,相关系数(r)为0.995 9～0.997 1。
化学还原体系中5种喹嗯啉类脱氧速率比较,为这类药物脱氧反应符合一级动力学规律提供判断依据。酸性碘化钾还原体系中,5种药物脱氧还原反应近似符合一级化学动力学规律,半衰期为4.80～19.06 min。碱性连二亚硫酸钠还原体系中喹噁啉类迅速还原,高效液相色谱测定反应体系,由其脱氧还原产物类别推测喹赛多脱氧速率最大,喹烯酮次之。化学还原体系中5种喹噁啉脱氧速率关系:喹赛多＞卡巴氧＞喹烯酮＞喹乙醇＞乙酰甲喹。
猪肝微粒体中5种喹噁啉类脱氧速率比较,验证喹噁啉类脱氧速率关系。5种药物在加有还原型辅酶的猪肝微粒体中孵育,高效液相色谱测定不同时间原形药物浓度,发现其脱氧还原反应符合一级化学动力学规律,5种药物的半衰期为11.75～69.31 min。脱氧速率喹赛多＞喹烯酮＞喹乙醇＞卡巴氧＞乙酰甲喹。
喹噁啉类脱氧速率及毒理学研究结果,进行脱氧速率与毒性相关性分析,证明脱氧速率为:喹赛多＞喹烯酮＞喹乙醇＞卡巴氧＞乙酰甲喹,速率越大毒性越低,脱氧速率与毒性之间存在负相关性,可以作为喹噁啉类毒性高低判断的重要参数,此结论可为喹噁啉类毒性作用机制研究提供理论依据。
本课题开展喹噁啉类分析方法和脱氧速率的研究,在国内外首次建立了饲料中多种喹噁啉类同时分析方法和不同动物可食性组织中喹噁啉类多残留分析方法,比较喹噁啉类脱氧速率快慢,分析脱氧速率与毒性大小之间的关系,这些研究为喹噁啉类残留监控和毒性机理研究提供了先进的检测方法和强有力的理论依据,对动物性食品安全评价有重要参考价值。
Quinoxalines are a group of synthetic antibacterial agents which are widely used as medicinal feed additives as antibacterial growth promoters.In some countries,carbadox and olaquindox have been banned or limited to be used in food animal due to their potential toxicity.Mequindox and quinocetone have been successively registered and the safer medicine of cyadox which belongs to quinoxalines family is being developed in China.However,it can not be neglected of the hazards from the residues on food safety for some abuse and illegal use of the drugs.So it is more important to do deep studies on toxicity mechanism of quinoxalines and analysis methods for determination of these drugs in feeds and animal foods.Though some methods have been reported for determination of the individual quinoxaline in simple matrix,no method has yet been developed for simultaneous determination of the five compounds in different matrices. And there is only suppose that toxicity is relative to desoxidation of the quinoxalines. However,no report is for clarifying relativity between deoxidation rates and toxicity of quinoxalines.Based on the two aspects,this study aims to explore analysis methods for determination of multi quinoxalines in feeds and animal edible tissues deeply,and investigate the relativity between deoxidation rates and toxicity of quinoxalines primarily, to provide technical support for monitoring and reasonable evidence for studying on toxicity mechanism of quinoxalines.The study also has a great value for evaluation on animal food safety.
1.Development of a method for simultaneous determination of the quinoxalines in feeds.
An HPLC method with UV detection has been established for simultaneous quantitative determination of the 5 quinoxalines(carbadox,olaquindox,cyadox, mequindox,quinocetone) in porcine,chicken and fish feeds.Feed samples were extracted with methanol-acetonitrile-water(35:35:30,v/v/v) in an ultrasonic bath,and purified by solid phase extraction on Alumina N cartridges.The samples were analyzed on an Eclipse XDB C_(18) liquid chromatography column using a gradient program with methanol and water.Except for cyadox(＞75%),recoveries of the drugs from feed samples spiked at 1, 5,50 and 200 mg/kg ranged from 92.1%to 104.3%.Coefficients of variation were 3.0%～13%.The decision limits(CCα) for the five compounds were＜0.45 mg/kg,and the detection capabilities(CCβ) were＜0.75 mg/kg.
The sample pretreatment has been simplified for using the ultrasonic extraction and solid phase extraction in the method.The volume of the organic solvent was decreased using the sample pretreatment method,and avoiding the toxicity solvent using in the method.In the same time,the interference peaks were deleted.The gradient elute of the mobile phase was used to separate five quinoxalines in a liquid column.The wavelength was set at 380 nm.In the experiment,the conditions for mobile phase and the wavelength have been investigated.
This simply and little contaminative method with the familiar materials can be applied on monitoring the use of multi-quinoxalines in porcine,chicken,fish feed,etc.This research can also provide reference for developing methods for determination of muti-ingredient in feeds.
2.Development of a method for simultaneous quantification of marker residues of quinoxalines in animal edible tissues.
A method of high-performance liquid chromatography with UV detection has been established for simultaneous quantitative determination of quinoxaline-2-carb- oxylic acid (QCA) and methyl-3-quinoxaline-2-carboxylic acid(MQCA),the marker residues for quinoxalines,respectively,in the muscles and livers of porcine and chicken and in the muscle of fish.And some conditions such as sample extraction,purification and sample solvent have been deeply investigated in this experiment.
Tissue samples were subject to acid hydrolysis followed by liquid-liquid extraction and Oasis MAX solid-phase extraction clean-up.Residues of concentration were solved with alkaline methanol and determined by high performance liquid chromatography with UV detection at wavelength of 320 nm.CCαwere 0.7～1.0μg/kg,CCβwere 1.3～1.7μg/kg for QCA and CCαwere 1.2～2.6μg/kg and CCβwere 2.0～4.4μg/kg for MQCA in muscle tissues.CCαwere 2.5～5.6μg/kg,CCβwere 4.3～5.6μg/kg for QCA and CCαwere 2.1～2.4μg/kg and CCβwere 4.4～5.6μg/kg for MQCA in liver tissues. Recoveries of QCA and MQCA,spiked in muscle tissues at levels of 2～16μg/kg,were from 70.7%to 104.3%,the relative standard deviation values were＜20%.Recoveries of QCA and MQCA,spiked in liver tissues at levels of 10～50μg/kg,were from 72.3%to 80.7%,the relative standard deviation values were＜13%.
This simple and sensitive method with little interference for the drugs can be applied to monitoring for the possible misuse of quinoxalines.The experiment can be taken as an instruction to do studies on analysis methods for determination of multi-residue in animal tissues and provide technical support for evaluation on animal food safety.
3.Comparative study on deoxidation rates of quinoxalines
To provide evidence for qualitative analysis of the productions from deoxidation of quinoxalines,HPLC with DAD detector was used to determine three desoxy compounds including desoxy cyadox,desoxy olaquindox and desoxy quinocetone.The detection limit was 0.01μmol/L and the quantitation limit was 0.02μmol/L.Within the range of 0.01～10μmol/L,the linearity relations between response and concentrations of three desoxy quinoxalines are good.The coefficient correlation(r) is 0.995 9 to 0.997 1.
Deoxidation rates of quinoxalines in chemical reductive systems were compared. The reaction in acid KI system was according with the first order kinetic equation.And half-lives of the five drugs were 4.80～19.06.In alkaline Na_2S_2O_4 system,deoxidation reaction was occurred immediately and the productions were determined by HPLC.From the results,it could be inferred that deoxidation rate of cyadox was the fastest among,and quinocetone is the second.In the chemical systems,it can be reduced that deoxidation rates of quinoxaliens are:cyadox＞carbadox＞quinocetone＞olaquindox＞mequindox.
Deoxidation rates of quinoxalines in porcine liver microsome reductive system were compared.The 5 drugs were incubated in porcine liver microsome with reducing type coenzyme.It is found that the reaction is also according to the first order rule and the half-lives were 11.75～69.31 min for the drugs.Deoxidation rates of quinoxaline drugs are:cyadox＞quinocetone＞olaquindox＞carbadox＞mequindox.
Above results are confirmed with toxicology experimental result of quinoxalines.It is proved that deoxidation rates of quinoxaline drugs are:cyadox＞quinocetone＞olaquindox＞carbadox＞mequindox.Toxic intensity of quinoxalines could be judged by their deoxidation rates.In a word,faster the rates,stronger the toxicity.The experiments could provide some reasonable evidences for study on toxicity mechanism of quinoxalines.
From above,analysis methods for determination of quinoxalines and toxicity mechanism of the drugs were studied in this paper circled on animal food safety.Analysis methods for determination of quinoxlaines in feeds and multi-residue of quinoxalines in animal edible tissues have been firstly established in this study.The relativity between deoxidation rates and toxicity of the drugs was illustrated,which could be one of judgments for toxicity level of the drugs.All the results from the study can provide advanced technologies and reasonable evidence for monitoring or residue surveillance for quinoxlaines and studying on toxicity mechanism of quinoxalines.And all of them have great vales for animal food safety.
1.饲料中喹噁啉类药物同时分析方法研究
深入探索样品前处理和检测方法,确定最佳条件,建立猪、鸡、鱼饲料中5种喹噁啉类高效液相色谱同时分析方法。样品经甲醇-水-乙腈(35:35:30,v/v/v)溶剂超声提取,中性氧化铝固相萃取小柱净化,高效液相色谱梯度洗脱分离,380 nm紫外波长测定。不同饲料样品中,5种药物的CCα小于0.45 mg/kg,CCβ小于0.75 mg/kg;在1、5、50和200 mg/kg的添加浓度,除喹赛多(＞75%)外,其它4种药物的回收率为92.1%～104.3%,日内、日间相对标准偏差为3.0%～13%。
超声提取和固相萃取净化,可以节省样品前处理时间,避免有毒试剂的使用,减少有机试剂用量,消除饲料基质对喹噁啉类药物测定干扰。仪器测定条件选择过程中,采用流动相梯度洗脱方式,考察了流动相成分和比例对5种喹噁啉类药物同时分析的影响,选用380 nm作为紫外检测器测定波长,进一步对5种喹噁啉类药物进行筛选,对比不同溶剂对药物测定分析结果差异,确定5种喹噁啉类药物同时分离分析的高效液相色谱条件。
本方法操作简便、材料易得、环境污染小,可以广泛应用于猪、鸡、鱼等饲料中多种喹噁啉类的监测,对饲料中其它化合物的多组分分析方法研究具有参考价值。
2.动物可食性组织中喹噁啉类多残留分析方法研究
探讨样品提取、净化和测定溶剂等条件,建立猪、鸡、鱼肌肉及猪、鸡肝脏组织中喹噁啉-2-羧酸和3-甲基喹噁啉-2-羧酸的高效液相色谱多残留分析方法。动物组织样品采用偏磷酸甲醇溶液水解,乙酸乙酯提取,MAX阴离子固相萃取小柱净化,碱性甲醇溶解浓缩残渣,高效液相色谱分离,320 nm紫外波长测定。猪、鸡、鱼肌肉组织中喹噁啉-2-羧酸的CCα为0.7～1.0μg/kg,CCβ为1.3～1.7μg/kg;3-甲基喹噁啉-2-羧酸的CCα为1.2～2.6μg/kg,CCβ为2.0～4.4μg/kg。猪、鸡肝脏组织中喹噁啉-2-羧酸的CCα为2.5～2.6μg/kg,CCβ为4.3～5.6μg/kg;3-甲基喹噁啉-2-羧酸的CCα为2.1～2.4μg/kg,CC∞为4.4～5.6μg/kg。喹噁啉-2-羧酸和3一甲基喹噁啉-2-羧酸在各动物肌肉组织中添加浓度为2.0～16μg/kg,回收率为70.7%～104.3%,相对标准偏差＜20%;在猪、鸡肝脏组织添加浓度为10～50μg/kg,回收率为72.3%～80.7%,相对标准偏差＜13%。
酸性环境水解样品,结合阴离子固相萃取小柱净化,简化了样品前处理步骤,避免强酸、强碱和有毒试剂的使用,可有效消除基质对药物测定的干扰,扩大了分析样品范围,方法灵敏度高。对比不同样品溶剂对两种分析物紫外吸收的影响,明确其经样品前处理后紫外吸收波长的变化,选用碱性甲醇溶剂,抵消了分析物紫外吸光度变化值,减小了回收率测定误差,提高了分析方法的准确度。
本方法样品前处理简单、基质干扰少、分析范围广、检测灵敏度高,基本达到国际领先水平,可广泛应用于喹噁啉类药物的残留监测,对动物组织中多残留分析方法研究具有指导意义,为动物性食品安全评价提供技术支持。
3.喹噁啉类脱氧速率研究
建立脱二氧喹赛多、脱二氧喹烯酮和脱二氧喹乙醇的高效液相色谱测定方法,为喹噁啉类脱氧产物定性分析提供技术方法。3种化合物经高效液相色谱流动相梯度洗脱分离,二极管阵列检测器测定,检测限为0.01μmol/L,定量限为0.02μmol/L,在0.01～10μmol/L范围内,线性关系良好,相关系数(r)为0.995 9～0.997 1。
化学还原体系中5种喹嗯啉类脱氧速率比较,为这类药物脱氧反应符合一级动力学规律提供判断依据。酸性碘化钾还原体系中,5种药物脱氧还原反应近似符合一级化学动力学规律,半衰期为4.80～19.06 min。碱性连二亚硫酸钠还原体系中喹噁啉类迅速还原,高效液相色谱测定反应体系,由其脱氧还原产物类别推测喹赛多脱氧速率最大,喹烯酮次之。化学还原体系中5种喹噁啉脱氧速率关系:喹赛多＞卡巴氧＞喹烯酮＞喹乙醇＞乙酰甲喹。
猪肝微粒体中5种喹噁啉类脱氧速率比较,验证喹噁啉类脱氧速率关系。5种药物在加有还原型辅酶的猪肝微粒体中孵育,高效液相色谱测定不同时间原形药物浓度,发现其脱氧还原反应符合一级化学动力学规律,5种药物的半衰期为11.75～69.31 min。脱氧速率喹赛多＞喹烯酮＞喹乙醇＞卡巴氧＞乙酰甲喹。
喹噁啉类脱氧速率及毒理学研究结果,进行脱氧速率与毒性相关性分析,证明脱氧速率为:喹赛多＞喹烯酮＞喹乙醇＞卡巴氧＞乙酰甲喹,速率越大毒性越低,脱氧速率与毒性之间存在负相关性,可以作为喹噁啉类毒性高低判断的重要参数,此结论可为喹噁啉类毒性作用机制研究提供理论依据。
本课题开展喹噁啉类分析方法和脱氧速率的研究,在国内外首次建立了饲料中多种喹噁啉类同时分析方法和不同动物可食性组织中喹噁啉类多残留分析方法,比较喹噁啉类脱氧速率快慢,分析脱氧速率与毒性大小之间的关系,这些研究为喹噁啉类残留监控和毒性机理研究提供了先进的检测方法和强有力的理论依据,对动物性食品安全评价有重要参考价值。
Quinoxalines are a group of synthetic antibacterial agents which are widely used as medicinal feed additives as antibacterial growth promoters.In some countries,carbadox and olaquindox have been banned or limited to be used in food animal due to their potential toxicity.Mequindox and quinocetone have been successively registered and the safer medicine of cyadox which belongs to quinoxalines family is being developed in China.However,it can not be neglected of the hazards from the residues on food safety for some abuse and illegal use of the drugs.So it is more important to do deep studies on toxicity mechanism of quinoxalines and analysis methods for determination of these drugs in feeds and animal foods.Though some methods have been reported for determination of the individual quinoxaline in simple matrix,no method has yet been developed for simultaneous determination of the five compounds in different matrices. And there is only suppose that toxicity is relative to desoxidation of the quinoxalines. However,no report is for clarifying relativity between deoxidation rates and toxicity of quinoxalines.Based on the two aspects,this study aims to explore analysis methods for determination of multi quinoxalines in feeds and animal edible tissues deeply,and investigate the relativity between deoxidation rates and toxicity of quinoxalines primarily, to provide technical support for monitoring and reasonable evidence for studying on toxicity mechanism of quinoxalines.The study also has a great value for evaluation on animal food safety.
1.Development of a method for simultaneous determination of the quinoxalines in feeds.
An HPLC method with UV detection has been established for simultaneous quantitative determination of the 5 quinoxalines(carbadox,olaquindox,cyadox, mequindox,quinocetone) in porcine,chicken and fish feeds.Feed samples were extracted with methanol-acetonitrile-water(35:35:30,v/v/v) in an ultrasonic bath,and purified by solid phase extraction on Alumina N cartridges.The samples were analyzed on an Eclipse XDB C_(18) liquid chromatography column using a gradient program with methanol and water.Except for cyadox(＞75%),recoveries of the drugs from feed samples spiked at 1, 5,50 and 200 mg/kg ranged from 92.1%to 104.3%.Coefficients of variation were 3.0%～13%.The decision limits(CCα) for the five compounds were＜0.45 mg/kg,and the detection capabilities(CCβ) were＜0.75 mg/kg.
The sample pretreatment has been simplified for using the ultrasonic extraction and solid phase extraction in the method.The volume of the organic solvent was decreased using the sample pretreatment method,and avoiding the toxicity solvent using in the method.In the same time,the interference peaks were deleted.The gradient elute of the mobile phase was used to separate five quinoxalines in a liquid column.The wavelength was set at 380 nm.In the experiment,the conditions for mobile phase and the wavelength have been investigated.
This simply and little contaminative method with the familiar materials can be applied on monitoring the use of multi-quinoxalines in porcine,chicken,fish feed,etc.This research can also provide reference for developing methods for determination of muti-ingredient in feeds.
2.Development of a method for simultaneous quantification of marker residues of quinoxalines in animal edible tissues.
A method of high-performance liquid chromatography with UV detection has been established for simultaneous quantitative determination of quinoxaline-2-carb- oxylic acid (QCA) and methyl-3-quinoxaline-2-carboxylic acid(MQCA),the marker residues for quinoxalines,respectively,in the muscles and livers of porcine and chicken and in the muscle of fish.And some conditions such as sample extraction,purification and sample solvent have been deeply investigated in this experiment.
Tissue samples were subject to acid hydrolysis followed by liquid-liquid extraction and Oasis MAX solid-phase extraction clean-up.Residues of concentration were solved with alkaline methanol and determined by high performance liquid chromatography with UV detection at wavelength of 320 nm.CCαwere 0.7～1.0μg/kg,CCβwere 1.3～1.7μg/kg for QCA and CCαwere 1.2～2.6μg/kg and CCβwere 2.0～4.4μg/kg for MQCA in muscle tissues.CCαwere 2.5～5.6μg/kg,CCβwere 4.3～5.6μg/kg for QCA and CCαwere 2.1～2.4μg/kg and CCβwere 4.4～5.6μg/kg for MQCA in liver tissues. Recoveries of QCA and MQCA,spiked in muscle tissues at levels of 2～16μg/kg,were from 70.7%to 104.3%,the relative standard deviation values were＜20%.Recoveries of QCA and MQCA,spiked in liver tissues at levels of 10～50μg/kg,were from 72.3%to 80.7%,the relative standard deviation values were＜13%.
This simple and sensitive method with little interference for the drugs can be applied to monitoring for the possible misuse of quinoxalines.The experiment can be taken as an instruction to do studies on analysis methods for determination of multi-residue in animal tissues and provide technical support for evaluation on animal food safety.
3.Comparative study on deoxidation rates of quinoxalines
To provide evidence for qualitative analysis of the productions from deoxidation of quinoxalines,HPLC with DAD detector was used to determine three desoxy compounds including desoxy cyadox,desoxy olaquindox and desoxy quinocetone.The detection limit was 0.01μmol/L and the quantitation limit was 0.02μmol/L.Within the range of 0.01～10μmol/L,the linearity relations between response and concentrations of three desoxy quinoxalines are good.The coefficient correlation(r) is 0.995 9 to 0.997 1.
Deoxidation rates of quinoxalines in chemical reductive systems were compared. The reaction in acid KI system was according with the first order kinetic equation.And half-lives of the five drugs were 4.80～19.06.In alkaline Na_2S_2O_4 system,deoxidation reaction was occurred immediately and the productions were determined by HPLC.From the results,it could be inferred that deoxidation rate of cyadox was the fastest among,and quinocetone is the second.In the chemical systems,it can be reduced that deoxidation rates of quinoxaliens are:cyadox＞carbadox＞quinocetone＞olaquindox＞mequindox.
Deoxidation rates of quinoxalines in porcine liver microsome reductive system were compared.The 5 drugs were incubated in porcine liver microsome with reducing type coenzyme.It is found that the reaction is also according to the first order rule and the half-lives were 11.75～69.31 min for the drugs.Deoxidation rates of quinoxaline drugs are:cyadox＞quinocetone＞olaquindox＞carbadox＞mequindox.
Above results are confirmed with toxicology experimental result of quinoxalines.It is proved that deoxidation rates of quinoxaline drugs are:cyadox＞quinocetone＞olaquindox＞carbadox＞mequindox.Toxic intensity of quinoxalines could be judged by their deoxidation rates.In a word,faster the rates,stronger the toxicity.The experiments could provide some reasonable evidences for study on toxicity mechanism of quinoxalines.
From above,analysis methods for determination of quinoxalines and toxicity mechanism of the drugs were studied in this paper circled on animal food safety.Analysis methods for determination of quinoxlaines in feeds and multi-residue of quinoxalines in animal edible tissues have been firstly established in this study.The relativity between deoxidation rates and toxicity of the drugs was illustrated,which could be one of judgments for toxicity level of the drugs.All the results from the study can provide advanced technologies and reasonable evidence for monitoring or residue surveillance for quinoxlaines and studying on toxicity mechanism of quinoxalines.And all of them have great vales for animal food safety.
引文
艾晓辉,刘长征.文华鱼组织中喹乙醇残留量高效液相色谱检测方法研究.湖北农学院学报,2003,23(4):266-270
曹随忠,张力,梁剑平,刘宗平.喹噁啉-1,4-二氧化物类抗菌促生长剂特殊毒理学研究进展.动物医学进展,2001,22(2):17-20
陈杖榴,杨桂香,孙永学,黄显会,曾振灵.兽药残留的毒性与生态毒理研究进展。华南农业大学学报,2001,22(1):88-91
雷德柱,高大维,于淑娟。超声波在食品技术中的应用.应用声学,2000,19(5):44-48
李家泰,李耘,王进.中国医院和社区获得性感染革兰阳性球菌耐药性监测研究.中华医学杂志,2003,83:365-374
李剑勇,李金善,徐忠赞,杜小丽,苗小楼,赵荣材,柳军席,薛飞群.喹烯酮在猪、鸡体内的药代动力学研究。畜牧兽医学报,2002,34(1):94-97
李剑勇,李金善,徐忠赞,赵荣材,苗小楼,张继瑜,鲁润华.高效液相色谱仪检测鸡组织器官喹烯酮残留方法的建立。动物医学进展,2004,25(5):100-101
李来生,邱水。高效液相色谱法测定饲料中的喹乙醇.色谱,1997,15(5):440-441
李来生,王宇晓,黄海珍.高效液相色谱法测定全价饲料中的喹乙醇.分析试验室,2000,19(3):19-21
李泰然.中国食源性疾病现状及管理建议.中华流行病学杂志,2003,24(8):651-653
牟世芬,刘勇建.加速溶剂萃取的原理及应用.现代科学仪器,2001,3:18-20
农业部办公厅文件.农办牧[2002]4号,2002
农业部畜牧兽医局编印。 中华人民共和国农业部公告第105号.北京:中国标准出版社,1999
农业部畜牧兽医局编印.中华人民共和国农业部公告第168号.北京:中国标准出版社,2001
农业部畜牧兽医局编印.中华人民共和国农业部公告第295号.北京:中国标准出版社,2003
农业部畜牧兽医局编印.中华人民共和国农业部公告第95号.北京:中国标准出版社,1998
欧阳华学,雷华越,汪开毓.测定饲料中喹乙醇含量的反相高效液相色谱法.分析测试学报,2002,21(3):73-75
邱银生,袁宗辉,范盛先,刘登才,黄玲利,殷居易。高效液相色谱法测定猪血浆及组织中喹赛多及脱二氧喹赛多代谢物。中国兽医学报,2003,23(4):363-365
邱银生.喹赛多在猪体内的药动学和残留研究.[博士学位论文].武汉:华中农业大学图书馆,2003
施杏芬,金海丽,陈勇,张志健,吕伟军.高效液相色谱法测定饲料中卡巴氧的含量。中国饲料,2004,13:34-35
王立.色谱分析样品处理。北京:化学工业出版社,2000,47-48
王树槐,徐士新.郑定.喹乙醇诱发小鼠骨髓嗜多染色体红细胞微核试验.中国兽医杂志,1991,1:13-14
王树槐。喹乙醇诱发细胞染色体畸变试验.中国兽医杂志,1993,27(4):27-29
王玉春,薛飞群,赵荣材,严相林,李金善,杜小丽,徐忠赞,张继瑜.喹烯酮在鸡体内的吸收与分布.中国兽医科技,1998,28(3):31-32
吴永宁,陈君石。食品安全重大专项,以风险分析为科学基础强化食品安全能力建设.中国食品安全(北京)论坛,2004
许国旺,杨军。代谢组学及其研究进展.色谱,2003,21(4):316-320
颜贤忠,赵剑宇,彭双清,廖明阳.代谢组学在后基因组时代的作用.波谱学杂志,2004,21(2):263-270
杨文军,张丽英,李德发,常碧影,王燕华,王宗义.反相高效液相色谱法测定饲料中喹乙醇的含量.中国兽药杂志,2003,37(2):20-23
曾振灵,董漓波,陈杖榴.喹乙醇在鸡组织的消除及残留研究.畜牧兽医学报.1995,26(4):327
张海霞,朱彭龄.固相萃取.分析化学,2000.28(9):1172-1180
张子仪.从科学发展观谈我国动物源食物安全生产中的若干问题。食品与药品,2005,7(2):7-10
中华人民共和国国家进出口商品检验局《食品分析大全》编写组.食品分析大全.北京:高等教育出版社,1997,9
周兵,李树文,张宏玲,简丽,程宗佳。不同淀粉含量饲料制粒后淀粉糊化度、水分、温度以及颗粒质量的变化初探.饲料广角,2006,8:24-26
NY/T438-2001.饲枓中盐酸克伦特罗的测定.农业部质量标准
NY/T727-2003.饲料中呋喃唑酮的测定-高效液相色谱法.农业部质量标准
Acree W E Joyce Jr,Powell Joyce R,Tucker Sheryl A,Ribeiro da Silva Maria D M C,Matos M Agostinha R,Goncalves J M,Santos L M N B F,Morals V M F,Pilcher G.Thermodchemical and theoretical study of some quinmoxaline 1,4-dioxides and of pyrazine 1,4-dioxide.Journal of Organic Chemistry,1997,62:3 722-3 726
Aerts M M,Beck W M,Keukens H J.Determination of residues of carbadox and some of its metabolites in swine tissues by high-performance liquid chromatography using on line pre-column enrichment and post-column derivatization with UV-VIS detection.Journal of Chromatography,1988,456(1):105-119
Antti Henrik,Ebbels M D Timothy,Keun Hector C,Bollard Mary E,Beckonert Olaf,Lindon John C,Nicholson Jeremy K,Holmes Elaine.Statistical experimental design and partial least squares regression analysis of biofluid metabonomic NMR and clinical chemistry data for screening of adverse drug effects.Chemometrics and Intelligent Laboratory Systems,2004,73:139-149
Aran i bar Nelly,Singh Bijay K,Stockton Gerald W,Karl-Heinz Ott.Automated Mode-of-Action Detection by Metabolic Profiling.Biochemical and Biophysical Research Communications,2001,286:150-155
Bailey Nigel J C,Oven Matjaz,Holmes Elaine,Nicholson Jeremy K,Zenk Meirthart H.Metabolomic analysis of the consequences of cadmium exposure in Silene cucubalus cell cultures via ~1H NMR spectroscopy and chemometrics.Phytochemistry,2003,62:851-858
Beulens A J M,Broens D F,Folstar P,Hofstede G J.Foodsafety and transparency in food chains and networks Relationships and challenges.Food Control,2005,16:481-486
Beutin L,Preller E,Kowalski B.Mutagenicity of quindoxin,its metabolites,and two substituted quinoxaline-di-oxides.Antimicrobial Agents and Chemotherapy,1981,20(3):336-343
Binnendijk G M,Aerts M M,Keukens H J,Brinkman U A.Optimization and ruggedness testing of the determination of residues of carbadox and metabolites in products of animal origin.Stability studies in animal tissues.Journal of Chromatography,1991,541(1-2):401-410
Blackledge C A,Nicholson J K,Wilson I D.An NMR study of the metabolic fate of 2-,3- and 4-fluorobenzyl alcohols in the rat detection of N-acetylcysteinyl conjugates as minor metabolites in urine. Journal of Pharmaceutical and Biomedical Analysis, 2003,32: 133-140
Boenke A, Searle C, Karjalainen T. Contribution of European research to endocrine disruptors. Analytka Chimica Acta, 2002, 473: 161-165
Boenke A. Contribution of European research to anti-microbials and hormones. Analytica Chimica Acta, 2002, 473: 83-87
Bosin T R, Maickel R P. Mass spectra of carcinogenic 4-hydroxylaminoquinoline n-oxides. Research Communication in Chemical Pathology Pharmacology, 1973, 6: 813-820
Botsoglou B A, Fletouris D J. Drug Residues in Foods Pharmacology, Food Safety, and Analysis, Marcel Dekker, New York, 2001 (Chapter 6)
Buchholz A, Hurlebaus J, Wandrey C, Takors R. Metabolomics: quantification of intracellular metabolite dynamics. Biomolecular Engineering, 2002, 19: 5-15
Bundy J G, Lenz E M, Bailey N J. Metabonomic investigation into the toxicity of 4-fluoroaniline, 3,5-difluoroaniline and 2-fluoro-4-methylaniline to the earthworm Eisenia veneta (Rosa): identification of novel endogenous biomarkers. Environmental Toxicology and Chemistry, 2002,21: 1 966-1 972
Cala P C, Trenner N R, Jack L, VandenHeuvel William J A. Determination of QCA in porcine liver by GC-ECD. Journal of Agricultral Food Chemistry, 1972, 20(2): 337-340
Cihak R, Vonotorkova M. Cytogenetic effects of quinoxaline-1, 4-dioxide-type growth promoting agents Ⅲ. Transplacental micronucleus in mice. Mutation Research, 1985,144:81-84
Cihak R, Vontorkova M. Cytogenetic effects of quinoxaline-1, 4-dioxide-type growth promoting agents Ⅱ, MetapHase analysis in mice. Mutatation Research, 1983, 117: 311-316
Claycamp H G, Hooberman B H. Antimicrobial resistance risk assessment in food safety. Journal of Food Protection, 2004, 67(9): 2 063-2 071
Commission Decision of 12 August 2002 implementing Council Directive 96/23/EC concerning the performance of analytical methods and the interpretation of results (2002/657/EC), Official J Eur Commun L221 (2002) 8.
Dalluge J J, Smith S, Sanchez-Riera F. Potential of fermentation profiling via rapid measurement of amino acid metabolism by liquid chromatography-tandem mass spectrometry. Journal of Chromatography A, 2004, 1043: 3-7
Diaz G J, Squires E J. Metabolism of 3-Methylindole by Porcine Liver Microsomes: Responsible Cytochrome P450 Enzymes. Toxicology Science, 2000, 55: 284-292
European Commission Draft Commission Decision implementing Council Directive 96/23/EC concerning the performance of analytical methods and the interpretation of results, 2002/657/EC
FAO/WHO. 36th Meeting of the Joint FAO/WHO Expert Committee on Food Additives, WHO Food Additives Series No. 27, 1991,141
FAO/WHO. Expert Committee on Food Additives: Evaluation of Certain Veterinary Drug Residues in Food, Technical Series NO. 799,1990,45
FAO/WHO. Forty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives. Toxicological evaluation of certain veterinary drug residues in food. WHO food additives series. WHO Rome, 1995, 33, 55-57
FAO/WHO. Forty-seventh report of the Joint FAO/WHO Expert Committee on Food Additives: Evaluation of certain veterinary drug residues in food, World Health Organ Technical Reporte Series NO. 876, 1998, 1-85
Ferrando R, Trubaut R, Raynaud J P. Relay toxicity. Ⅲ Safety for the human consumer of the use of carbadox, a feed additive for swine, as estimated by a 7 years relay toxicity study on digs. Toxicology, 1978, 11(2): 167-183
Fiehn O. Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks. Comparative and Functional Genomics, 2001, 2(3): 155-168
Fiehn O. Metabolomics-the link between genotypes and phenotypes. Plant Molecular Biology Reporter, 2002, 48: 155-168
Figdor S K. Carbadox in Pigs Radiotracer Metabolism C~(14)-Carbonyl (1969). Unpublished. Submitted to WHO by Pfizer Central Research, Groton, CT, USA.
Ganley B, Chowdhury G, Bhansali J, Daniels J S, Gates K S, Redox-activated, hypoxia-selective DNA by quinoxaline-1, 4-di-N-oxide. Bioorganic and Medicinal Chemistry, 2001, 9: 2 395-2 400
Graaf G J, Spierenbxlrg T J. Liquid chromatographic determination of carbadox and desoxycarbadox in medicated feeds and in porcine gastrointesrinal tract. Journal of AOAC international, 1985, 68(4): 658-660
Grivet J P, Delort A M, Portais J C. NMR and microbiology: fromphysiology to metabolomics. Biochimie, 2003, 85: 823-840
Hall R, Beale M, Fiehn O, Harly N, Summer L, Bino R. Plant metabolomics: the missing link in functional genomics strategies. Plant Cell, 2002, 14: 1 437-1 440
Harrigan George G, LaPlante Roxanne H, Cosma Greg N, Gary Cockerell, Royston Goodacre, Maddox Jane F, Luyendyk James P, Ganey Patricia E, Roth Robert A. Application ofhigh-throughput Fourier-transforminfrared spectroscopyin toxicology studies: contribution to a study on the developmentof an animal model for idiosyncratic toxicity. Toxicology Letters, 2004, 146: 197-205
Horie M, Murayama M. Determination of carbadox metabolites, quinoxaline-2-carboxylic acid and desoxycarbadox, in swine muscle and liver by liquid chromatography/mass spectrometry. Shokuhin Eiseigaku Zasshi, 2004, 45(3): 135-140
Hutchinson M J, Young P B, Kennedy D G. Confirmations of carbadox and olaquindox metabolites in porcine liver using liquid chromatography-electrospray, tandem mass spectrometrometry. Journal of Chromatography B, 2005, 816(1-2): 15-20
Hutchinson M J, Young P Y, Hewitt S A, Faulkner D, Kennedy D G. Development and validation of an improved method for confirmation of the carbdox metabolite, quinoxaline-2-carboxylic acid, in porcine liver using LC-electrospary MS-MS according to revised EU criteria for veterinary drug residue analysis. Analyst, 2002, 127: 342-346
ISO 11843-1. International Organisation for Standardization, Geneva, Switzerland, 1997, 1
ISO 14939. Animal feeding stuffs. Determination of carbadox content. Method using high performance liquid chromatography, 2001
Ivana S, Miloslav K. Determination of cyadox and its metabolites in plasma by adsorptive voltammetry. Talanta, 1988, 35(10): 816-818
Jonsson P, Gullberg J, Nordstrom A, KusanoM, KowalczykM, SjostromM, MoritzT. A strategy for identifying differences in large series of metabolomic samples analyzed by GC/MS. Analytical Chemistry, 2004, 76(6): 1 738-1 745
Jonsson P, Johansson A I, Gullberg J, Trygg J A J, Grung B, Marklund S, Sjostrom M, AnttiH, Moritz T. High-throughput data analysis for detecting and identifying differences between samples in GC/MS based metabolomic analyses. Analytical Chemistry, 2005, 77(17): 5 635-5 642
Kaferstein F. Food borne diseases in developing countries: aetiology epidemiology and strategies for prevention. International Journal of Environment Health Research, 2003, 1: 161-168
Kiese M. IARC reviewed the genetic effects of nitrobenzene. Pharmacological Reviews, 1996, 18: 1091-1 161
Lafayea, Junotc, Gall B R. Metabolite profiling in rat urine by liquid chromatography/ electrospray ion trapmass spectrometry application to the study of heavy metal toxicity. Rapid Communication Mass Spectrom, 2003, 17: 2 541-2 549
Lauridsen M G, Lund C, Jacobsen M. Determination and depletion of residues of carbadox, tylosin, and virginiamycin in kidney, liver, and muscle of pigs in feeding experiments. Journal of AOAC international, 1988, 71(5): 921-925
Lenz E M, Bright J, Knight R, Wilson I D, Major H. Cyclosporin A-induced changes inendogenous metabolites in rat urine: a metabonomicinvestigation usinghigh field ~1H NMR spectroscopy, HPLC-TOF/MS and chemometrics. Journal of Pharmaceutical and Biomedical Analysis, 2004a, 35: 599-608
Lenz E M, Bright J, Wilson I D, Hughes A, Morrisson J, Lindberg H, Lockton A. Metabonomics, dietary influences and cultural differences: ~1H NMR-based study ofurine samples obtained from healthy British and Swedish subjects. Journal of Pharmaceutical and Biomedical Analysis, 2004b, 36: 841-849
Lin S Y, Jeng S L. High-performance liquid chromatographic determination of carbadox, olaquindox, furazolidone, nitrofurazone, and nitrovin in feed. Journal of Food Protection, 2001, 64(8): 1 231-1 234
Lowie D M Jr, Teague R T Jr, Quick F E, Foster C L. High pressure liquid chromatographic determination of carbadox and pyrantel tartrate in swine feed and supplements. Journal of AOAC international, 1983, 66(3): 602-605
Lynch M J, Bartolucci S R. Confirmatory identification of carbadox-related residies in swine liver by Gas-Liquid Chromatography/Mass Spectrometry with Selected Ion Monitoring. Journal of AOAC international, 1982, 65(1): 66-70
Lynch M J, Mosher F R, Schneider R P. Determination of carbadox-related residues in swine liver by gas-chromatography/mass spectrometry with ion trap detection. Journal of AOAC international, 1991, 74(4): 611-617
Macintosh A I and Neville G A. Liquid chromatographic determination of carbadox, desoxycarbadox, and nitrofurazones in pork tissues. Journal of AOAC international, 1984, 67(5): 958-962
Maul W, Seng F, Wendisch D. Investigations into the biotransformation of olaquinox in swine. Report No. 8725. Unpublished report from Bayer AG, Wuppertal-Elberfeld, FRG. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG. 1979b
Maul W, Seng F, Wendisch D. Investigations into the biotransformation of olaquinox in swine. Report No. 8114. Unpublished report from Bayer AG, Wuppertal-Elberfeld, FRG. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG. 1979a
McGary E D. Quantitative determination of sulphamethazine and carbadox in animal feeds by paired ion high-performance liquid. Analyst, 1986, 111(11): 1341-1342
NADA No.41-061. Total Residue and Metabolism Studies. 1998.1
Nagata T, Saeki M. Determination of olaquindox residues in swine tissues by liquid chromatography. Journal of AOAC international, 1987,70(4): 706-707
Nicholson J K, Connelly J, Lindon J C, Holmes E. Metabonomics: a platfoor for studying drug toxicity and gene function. Nature Reviews Drug Discovery, 2002, 1(2): 153-161
Nicholson J K, Lindon J C, Holmes E. 'Metabonomics1: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR data. Xenobiotica, 1999,29(11): 1 181-1 189
Novavek L, Semenkova L, Holtk M. Deoxidation of quinoxalie-1,4-dioxide derivative in the presence of amino acids. Journal of Cesk Farm, 1986, 35 (4): 145-150
Pham-Tuan H, Kaskavelis L, Daykin C A, Janssen H G. Method development in high-performance liquid chromatography for high-throughput profiling and metabonomic studies of biofluid samples. Journal of Chromatography B, 2003, 789(2): 283-301
Poucke V C, Keyser D K, Baltusnikiene A, McEvoy J D G, Peteghem V C. Liquid chromatographic tandem spectrometric detection of banned antibacterial growth promoters in animal feed. Analytical Chimica Acta, 2003, 483: 99-109
Power S B, Donnelly W J, McLaughlin J G, Walsh M C, Dromey M F. Accidental carbadox overdosage in pigs in an Irish weaner-producing herd. Veterinary Record, 1989, 124(14): 367-370
Ramos D F J, Silveira D I N, Graaf D G. Column liquid chromatographic determination of carbadox and olaquindox in feeds. Journal of Chromatography, 1991, 558(1): 125-130
Rose M D, Bygrave J, Tarbin J A. Determination of quinoxaline carboxylic acid (metabolite of carbadox) in animal tissue by HPLC. Food Addition Contamination, 1995, 12(2): 177-183
Roybal J E, Munns R K, Shimoda W. Liquid chromatographic determination of carbadox residues in animal feed. Journal of AOAC international, 1985, 68(4): 653-657
Rutalj M, Bazulic D, Sapunar-Postruznik J. Quinoxaline-2-carboxylic acid (QCA) in swine liver and muscle. Food Additives and Contaminants, 1996, 13(8): 879-882
Scheutwinkel-Rrich M, VonDer H W. Sister-chromatid exchange in Chinese hamster V79 cells exposed to quindoxin, carbadox and olaquindox. Mutation Research, 1984, 139(4): 199-202
Sestakova I, Skarka P, Manousek 0, Determination of QCA in porcine liver by polar-graphic. Journal of Biological Chemistry, 1988,16(22): 29-32
Sin D W M, Chung L P K, Lai M M C, Siu S M P, Tang H P 0. Determination of quinoxaline-2-carboxylic acid, themajor metabolite of carbadox, in porcine liverbyisotope dilution gas chromatography-electron capturenegative ionization mass spectrometry. Analytical Chimica Acta, 2004, 508(2): 147-158
Slim R M, Robertson D G, Albassam M, Reily M D, Robosky L, Dethloff L A. Metabonomics, dietary influences and cultural differences: a ~1H NMR-based study of urine samples obtained from healthy British and Swedish subjects. Toxicology and Applied Pharmacology, 2002, 183(2): 108-109
Smith Lewis L. Key challenges for toxicologists in the 21st century. Trends in Pharmacological Sciences, 2001, 22(6): 281-285
Spierenburg T J, Lenthe V H, Graaf D G, Jager L P. Liquid chromatographic determination of olaquindox in medicated feeds and in contents of porcine gastrointestinal tract. Journal of AOAC international, 1988,71(6): 1 106-1 109
Sram R J, Salome F R, Jaroslava K. Dominant lethal mutation in female mice after oral administration of cyadox and olaquindox. Biologizace A Chemizace Zivocisne Vyroby Veterinaria, 1986, 22(1): 29-35
Stanley E G, Bailey N J, Bollard M E, Haselden J N, Waterfield C J, Holmes E, Nicholson J K. Sexual dimorphism in urinary metabolite profiles of Han Wistar rats revealed by nuclear-magnetic-resonance-based metabonomics. Analytical Biochemistry, 2005, 343(2): 195-202
Sugimoto M, Kikuchi S, AritaM, Soga T, Nishioka T, TomitaM. Large-scale prediction of cationic metabolite identity and migration time in capillary electrophoresis mass spectrometry using artificial neural networks. Analytical Chemistry, 2005, 77(1): 78-84
Sykora I, Marhan O, Gandalovicova D. Effects of the nonantibiotic growth stimulators carbdox and cyadox on reproduction in laboratory animals. Veterinarni Medicina, 1981, 26(6): 367-377
Tarra Fuchs, Kent S Gates, Jae-Taeg Hwang, Marc M. Greenberg Photosensitization of Guanine-Specific DNA Damage by a Cyano-Substituted Quinoxaline Di-N-oxide. Greenberg Chemical research toxicology, 1999, 12: 1 190-1 194
Taylor J, King R D, AltmannT, Fiehn O. Application of metabolomics to plant genotype discrimination using statistics and machine learning. Bioinformatics, 2002, 18: 241-248
Tennant R W. The National Center for Toxicogenomics: using new technologies to inform mechanistic toxicology. Environment Health Perspective, 2002, 110: 8-11
Thorpe V A. A collaborative study: high-pressure liquid chromatographic determination of carbadox and pyrantel tartrate in animal feeds. Journal of Chromatography Science, 1988, 26(11): 545-550
Thorpe V A. Rapid colorimetric method for carbadox in animal feeds. Journal of AOAC international, 1976, 59(6): 1 290-1 293
Tolstikov V V, Lommen A, Nakanishi K, Tanaka N, Fiehn O. Monolithic Silica-Based Capillary Reversed-Phase Liquid Chromatography/Electrospray Mass Spectrometry for Plant Metabolomics. Analytical Chemistry, 2003, 75(23): 6 737-6 740
Vanova L, Kolouch F, Sevcik B. The action of cyadox on rabbit reproduction. Biological Chemistry Zivocisne Vyroby-Veterinary, 1986, 22(1): 47-52
Voogd C E, Van D J J. The mutagenic action of quindoxin, carbadox, olaquindox and some other N-Oxide on bacteria and yeast. Mutation Research, 1980, 78(3): 233-242
Wu Y J, Wang Y L, Huang L L, Tao Y F, Yuan Z H, Chen D M. Simultaneous determination of five quinoxaline-1, 4-dioxides in animal feeds using ultrasonic solvent extraction and high-performance liquid chromatography. Analytical Chimica Acta, 2006, 569(1-2): 97-102
Yang J, Xu G W, Zheng Y F, Kong H W, Pang T, Lv S, Yang Q. Diagnosis of liver cancer using HPLC-based metabonomics avoiding false-positive resultfrom hepatitis and hepatocirrhosis diseases. Journal of Chromatography B, 2004, 813: 59-65
Yoshimura H, Nakmura M, Koeda T. Mutagenicities of carbadox and olaquindox growth promoters for pigs. Mutation Research, 1981, 90: 49-55
曹随忠,张力,梁剑平,刘宗平.喹噁啉-1,4-二氧化物类抗菌促生长剂特殊毒理学研究进展.动物医学进展,2001,22(2):17-20
陈杖榴,杨桂香,孙永学,黄显会,曾振灵.兽药残留的毒性与生态毒理研究进展。华南农业大学学报,2001,22(1):88-91
雷德柱,高大维,于淑娟。超声波在食品技术中的应用.应用声学,2000,19(5):44-48
李家泰,李耘,王进.中国医院和社区获得性感染革兰阳性球菌耐药性监测研究.中华医学杂志,2003,83:365-374
李剑勇,李金善,徐忠赞,杜小丽,苗小楼,赵荣材,柳军席,薛飞群.喹烯酮在猪、鸡体内的药代动力学研究。畜牧兽医学报,2002,34(1):94-97
李剑勇,李金善,徐忠赞,赵荣材,苗小楼,张继瑜,鲁润华.高效液相色谱仪检测鸡组织器官喹烯酮残留方法的建立。动物医学进展,2004,25(5):100-101
李来生,邱水。高效液相色谱法测定饲料中的喹乙醇.色谱,1997,15(5):440-441
李来生,王宇晓,黄海珍.高效液相色谱法测定全价饲料中的喹乙醇.分析试验室,2000,19(3):19-21
李泰然.中国食源性疾病现状及管理建议.中华流行病学杂志,2003,24(8):651-653
牟世芬,刘勇建.加速溶剂萃取的原理及应用.现代科学仪器,2001,3:18-20
农业部办公厅文件.农办牧[2002]4号,2002
农业部畜牧兽医局编印。 中华人民共和国农业部公告第105号.北京:中国标准出版社,1999
农业部畜牧兽医局编印.中华人民共和国农业部公告第168号.北京:中国标准出版社,2001
农业部畜牧兽医局编印.中华人民共和国农业部公告第295号.北京:中国标准出版社,2003
农业部畜牧兽医局编印.中华人民共和国农业部公告第95号.北京:中国标准出版社,1998
欧阳华学,雷华越,汪开毓.测定饲料中喹乙醇含量的反相高效液相色谱法.分析测试学报,2002,21(3):73-75
邱银生,袁宗辉,范盛先,刘登才,黄玲利,殷居易。高效液相色谱法测定猪血浆及组织中喹赛多及脱二氧喹赛多代谢物。中国兽医学报,2003,23(4):363-365
邱银生.喹赛多在猪体内的药动学和残留研究.[博士学位论文].武汉:华中农业大学图书馆,2003
施杏芬,金海丽,陈勇,张志健,吕伟军.高效液相色谱法测定饲料中卡巴氧的含量。中国饲料,2004,13:34-35
王立.色谱分析样品处理。北京:化学工业出版社,2000,47-48
王树槐,徐士新.郑定.喹乙醇诱发小鼠骨髓嗜多染色体红细胞微核试验.中国兽医杂志,1991,1:13-14
王树槐。喹乙醇诱发细胞染色体畸变试验.中国兽医杂志,1993,27(4):27-29
王玉春,薛飞群,赵荣材,严相林,李金善,杜小丽,徐忠赞,张继瑜.喹烯酮在鸡体内的吸收与分布.中国兽医科技,1998,28(3):31-32
吴永宁,陈君石。食品安全重大专项,以风险分析为科学基础强化食品安全能力建设.中国食品安全(北京)论坛,2004
许国旺,杨军。代谢组学及其研究进展.色谱,2003,21(4):316-320
颜贤忠,赵剑宇,彭双清,廖明阳.代谢组学在后基因组时代的作用.波谱学杂志,2004,21(2):263-270
杨文军,张丽英,李德发,常碧影,王燕华,王宗义.反相高效液相色谱法测定饲料中喹乙醇的含量.中国兽药杂志,2003,37(2):20-23
曾振灵,董漓波,陈杖榴.喹乙醇在鸡组织的消除及残留研究.畜牧兽医学报.1995,26(4):327
张海霞,朱彭龄.固相萃取.分析化学,2000.28(9):1172-1180
张子仪.从科学发展观谈我国动物源食物安全生产中的若干问题。食品与药品,2005,7(2):7-10
中华人民共和国国家进出口商品检验局《食品分析大全》编写组.食品分析大全.北京:高等教育出版社,1997,9
周兵,李树文,张宏玲,简丽,程宗佳。不同淀粉含量饲料制粒后淀粉糊化度、水分、温度以及颗粒质量的变化初探.饲料广角,2006,8:24-26
NY/T438-2001.饲枓中盐酸克伦特罗的测定.农业部质量标准
NY/T727-2003.饲料中呋喃唑酮的测定-高效液相色谱法.农业部质量标准
Acree W E Joyce Jr,Powell Joyce R,Tucker Sheryl A,Ribeiro da Silva Maria D M C,Matos M Agostinha R,Goncalves J M,Santos L M N B F,Morals V M F,Pilcher G.Thermodchemical and theoretical study of some quinmoxaline 1,4-dioxides and of pyrazine 1,4-dioxide.Journal of Organic Chemistry,1997,62:3 722-3 726
Aerts M M,Beck W M,Keukens H J.Determination of residues of carbadox and some of its metabolites in swine tissues by high-performance liquid chromatography using on line pre-column enrichment and post-column derivatization with UV-VIS detection.Journal of Chromatography,1988,456(1):105-119
Antti Henrik,Ebbels M D Timothy,Keun Hector C,Bollard Mary E,Beckonert Olaf,Lindon John C,Nicholson Jeremy K,Holmes Elaine.Statistical experimental design and partial least squares regression analysis of biofluid metabonomic NMR and clinical chemistry data for screening of adverse drug effects.Chemometrics and Intelligent Laboratory Systems,2004,73:139-149
Aran i bar Nelly,Singh Bijay K,Stockton Gerald W,Karl-Heinz Ott.Automated Mode-of-Action Detection by Metabolic Profiling.Biochemical and Biophysical Research Communications,2001,286:150-155
Bailey Nigel J C,Oven Matjaz,Holmes Elaine,Nicholson Jeremy K,Zenk Meirthart H.Metabolomic analysis of the consequences of cadmium exposure in Silene cucubalus cell cultures via ~1H NMR spectroscopy and chemometrics.Phytochemistry,2003,62:851-858
Beulens A J M,Broens D F,Folstar P,Hofstede G J.Foodsafety and transparency in food chains and networks Relationships and challenges.Food Control,2005,16:481-486
Beutin L,Preller E,Kowalski B.Mutagenicity of quindoxin,its metabolites,and two substituted quinoxaline-di-oxides.Antimicrobial Agents and Chemotherapy,1981,20(3):336-343
Binnendijk G M,Aerts M M,Keukens H J,Brinkman U A.Optimization and ruggedness testing of the determination of residues of carbadox and metabolites in products of animal origin.Stability studies in animal tissues.Journal of Chromatography,1991,541(1-2):401-410
Blackledge C A,Nicholson J K,Wilson I D.An NMR study of the metabolic fate of 2-,3- and 4-fluorobenzyl alcohols in the rat detection of N-acetylcysteinyl conjugates as minor metabolites in urine. Journal of Pharmaceutical and Biomedical Analysis, 2003,32: 133-140
Boenke A, Searle C, Karjalainen T. Contribution of European research to endocrine disruptors. Analytka Chimica Acta, 2002, 473: 161-165
Boenke A. Contribution of European research to anti-microbials and hormones. Analytica Chimica Acta, 2002, 473: 83-87
Bosin T R, Maickel R P. Mass spectra of carcinogenic 4-hydroxylaminoquinoline n-oxides. Research Communication in Chemical Pathology Pharmacology, 1973, 6: 813-820
Botsoglou B A, Fletouris D J. Drug Residues in Foods Pharmacology, Food Safety, and Analysis, Marcel Dekker, New York, 2001 (Chapter 6)
Buchholz A, Hurlebaus J, Wandrey C, Takors R. Metabolomics: quantification of intracellular metabolite dynamics. Biomolecular Engineering, 2002, 19: 5-15
Bundy J G, Lenz E M, Bailey N J. Metabonomic investigation into the toxicity of 4-fluoroaniline, 3,5-difluoroaniline and 2-fluoro-4-methylaniline to the earthworm Eisenia veneta (Rosa): identification of novel endogenous biomarkers. Environmental Toxicology and Chemistry, 2002,21: 1 966-1 972
Cala P C, Trenner N R, Jack L, VandenHeuvel William J A. Determination of QCA in porcine liver by GC-ECD. Journal of Agricultral Food Chemistry, 1972, 20(2): 337-340
Cihak R, Vonotorkova M. Cytogenetic effects of quinoxaline-1, 4-dioxide-type growth promoting agents Ⅲ. Transplacental micronucleus in mice. Mutation Research, 1985,144:81-84
Cihak R, Vontorkova M. Cytogenetic effects of quinoxaline-1, 4-dioxide-type growth promoting agents Ⅱ, MetapHase analysis in mice. Mutatation Research, 1983, 117: 311-316
Claycamp H G, Hooberman B H. Antimicrobial resistance risk assessment in food safety. Journal of Food Protection, 2004, 67(9): 2 063-2 071
Commission Decision of 12 August 2002 implementing Council Directive 96/23/EC concerning the performance of analytical methods and the interpretation of results (2002/657/EC), Official J Eur Commun L221 (2002) 8.
Dalluge J J, Smith S, Sanchez-Riera F. Potential of fermentation profiling via rapid measurement of amino acid metabolism by liquid chromatography-tandem mass spectrometry. Journal of Chromatography A, 2004, 1043: 3-7
Diaz G J, Squires E J. Metabolism of 3-Methylindole by Porcine Liver Microsomes: Responsible Cytochrome P450 Enzymes. Toxicology Science, 2000, 55: 284-292
European Commission Draft Commission Decision implementing Council Directive 96/23/EC concerning the performance of analytical methods and the interpretation of results, 2002/657/EC
FAO/WHO. 36th Meeting of the Joint FAO/WHO Expert Committee on Food Additives, WHO Food Additives Series No. 27, 1991,141
FAO/WHO. Expert Committee on Food Additives: Evaluation of Certain Veterinary Drug Residues in Food, Technical Series NO. 799,1990,45
FAO/WHO. Forty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives. Toxicological evaluation of certain veterinary drug residues in food. WHO food additives series. WHO Rome, 1995, 33, 55-57
FAO/WHO. Forty-seventh report of the Joint FAO/WHO Expert Committee on Food Additives: Evaluation of certain veterinary drug residues in food, World Health Organ Technical Reporte Series NO. 876, 1998, 1-85
Ferrando R, Trubaut R, Raynaud J P. Relay toxicity. Ⅲ Safety for the human consumer of the use of carbadox, a feed additive for swine, as estimated by a 7 years relay toxicity study on digs. Toxicology, 1978, 11(2): 167-183
Fiehn O. Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks. Comparative and Functional Genomics, 2001, 2(3): 155-168
Fiehn O. Metabolomics-the link between genotypes and phenotypes. Plant Molecular Biology Reporter, 2002, 48: 155-168
Figdor S K. Carbadox in Pigs Radiotracer Metabolism C~(14)-Carbonyl (1969). Unpublished. Submitted to WHO by Pfizer Central Research, Groton, CT, USA.
Ganley B, Chowdhury G, Bhansali J, Daniels J S, Gates K S, Redox-activated, hypoxia-selective DNA by quinoxaline-1, 4-di-N-oxide. Bioorganic and Medicinal Chemistry, 2001, 9: 2 395-2 400
Graaf G J, Spierenbxlrg T J. Liquid chromatographic determination of carbadox and desoxycarbadox in medicated feeds and in porcine gastrointesrinal tract. Journal of AOAC international, 1985, 68(4): 658-660
Grivet J P, Delort A M, Portais J C. NMR and microbiology: fromphysiology to metabolomics. Biochimie, 2003, 85: 823-840
Hall R, Beale M, Fiehn O, Harly N, Summer L, Bino R. Plant metabolomics: the missing link in functional genomics strategies. Plant Cell, 2002, 14: 1 437-1 440
Harrigan George G, LaPlante Roxanne H, Cosma Greg N, Gary Cockerell, Royston Goodacre, Maddox Jane F, Luyendyk James P, Ganey Patricia E, Roth Robert A. Application ofhigh-throughput Fourier-transforminfrared spectroscopyin toxicology studies: contribution to a study on the developmentof an animal model for idiosyncratic toxicity. Toxicology Letters, 2004, 146: 197-205
Horie M, Murayama M. Determination of carbadox metabolites, quinoxaline-2-carboxylic acid and desoxycarbadox, in swine muscle and liver by liquid chromatography/mass spectrometry. Shokuhin Eiseigaku Zasshi, 2004, 45(3): 135-140
Hutchinson M J, Young P B, Kennedy D G. Confirmations of carbadox and olaquindox metabolites in porcine liver using liquid chromatography-electrospray, tandem mass spectrometrometry. Journal of Chromatography B, 2005, 816(1-2): 15-20
Hutchinson M J, Young P Y, Hewitt S A, Faulkner D, Kennedy D G. Development and validation of an improved method for confirmation of the carbdox metabolite, quinoxaline-2-carboxylic acid, in porcine liver using LC-electrospary MS-MS according to revised EU criteria for veterinary drug residue analysis. Analyst, 2002, 127: 342-346
ISO 11843-1. International Organisation for Standardization, Geneva, Switzerland, 1997, 1
ISO 14939. Animal feeding stuffs. Determination of carbadox content. Method using high performance liquid chromatography, 2001
Ivana S, Miloslav K. Determination of cyadox and its metabolites in plasma by adsorptive voltammetry. Talanta, 1988, 35(10): 816-818
Jonsson P, Gullberg J, Nordstrom A, KusanoM, KowalczykM, SjostromM, MoritzT. A strategy for identifying differences in large series of metabolomic samples analyzed by GC/MS. Analytical Chemistry, 2004, 76(6): 1 738-1 745
Jonsson P, Johansson A I, Gullberg J, Trygg J A J, Grung B, Marklund S, Sjostrom M, AnttiH, Moritz T. High-throughput data analysis for detecting and identifying differences between samples in GC/MS based metabolomic analyses. Analytical Chemistry, 2005, 77(17): 5 635-5 642
Kaferstein F. Food borne diseases in developing countries: aetiology epidemiology and strategies for prevention. International Journal of Environment Health Research, 2003, 1: 161-168
Kiese M. IARC reviewed the genetic effects of nitrobenzene. Pharmacological Reviews, 1996, 18: 1091-1 161
Lafayea, Junotc, Gall B R. Metabolite profiling in rat urine by liquid chromatography/ electrospray ion trapmass spectrometry application to the study of heavy metal toxicity. Rapid Communication Mass Spectrom, 2003, 17: 2 541-2 549
Lauridsen M G, Lund C, Jacobsen M. Determination and depletion of residues of carbadox, tylosin, and virginiamycin in kidney, liver, and muscle of pigs in feeding experiments. Journal of AOAC international, 1988, 71(5): 921-925
Lenz E M, Bright J, Knight R, Wilson I D, Major H. Cyclosporin A-induced changes inendogenous metabolites in rat urine: a metabonomicinvestigation usinghigh field ~1H NMR spectroscopy, HPLC-TOF/MS and chemometrics. Journal of Pharmaceutical and Biomedical Analysis, 2004a, 35: 599-608
Lenz E M, Bright J, Wilson I D, Hughes A, Morrisson J, Lindberg H, Lockton A. Metabonomics, dietary influences and cultural differences: ~1H NMR-based study ofurine samples obtained from healthy British and Swedish subjects. Journal of Pharmaceutical and Biomedical Analysis, 2004b, 36: 841-849
Lin S Y, Jeng S L. High-performance liquid chromatographic determination of carbadox, olaquindox, furazolidone, nitrofurazone, and nitrovin in feed. Journal of Food Protection, 2001, 64(8): 1 231-1 234
Lowie D M Jr, Teague R T Jr, Quick F E, Foster C L. High pressure liquid chromatographic determination of carbadox and pyrantel tartrate in swine feed and supplements. Journal of AOAC international, 1983, 66(3): 602-605
Lynch M J, Bartolucci S R. Confirmatory identification of carbadox-related residies in swine liver by Gas-Liquid Chromatography/Mass Spectrometry with Selected Ion Monitoring. Journal of AOAC international, 1982, 65(1): 66-70
Lynch M J, Mosher F R, Schneider R P. Determination of carbadox-related residues in swine liver by gas-chromatography/mass spectrometry with ion trap detection. Journal of AOAC international, 1991, 74(4): 611-617
Macintosh A I and Neville G A. Liquid chromatographic determination of carbadox, desoxycarbadox, and nitrofurazones in pork tissues. Journal of AOAC international, 1984, 67(5): 958-962
Maul W, Seng F, Wendisch D. Investigations into the biotransformation of olaquinox in swine. Report No. 8725. Unpublished report from Bayer AG, Wuppertal-Elberfeld, FRG. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG. 1979b
Maul W, Seng F, Wendisch D. Investigations into the biotransformation of olaquinox in swine. Report No. 8114. Unpublished report from Bayer AG, Wuppertal-Elberfeld, FRG. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG. 1979a
McGary E D. Quantitative determination of sulphamethazine and carbadox in animal feeds by paired ion high-performance liquid. Analyst, 1986, 111(11): 1341-1342
NADA No.41-061. Total Residue and Metabolism Studies. 1998.1
Nagata T, Saeki M. Determination of olaquindox residues in swine tissues by liquid chromatography. Journal of AOAC international, 1987,70(4): 706-707
Nicholson J K, Connelly J, Lindon J C, Holmes E. Metabonomics: a platfoor for studying drug toxicity and gene function. Nature Reviews Drug Discovery, 2002, 1(2): 153-161
Nicholson J K, Lindon J C, Holmes E. 'Metabonomics1: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR data. Xenobiotica, 1999,29(11): 1 181-1 189
Novavek L, Semenkova L, Holtk M. Deoxidation of quinoxalie-1,4-dioxide derivative in the presence of amino acids. Journal of Cesk Farm, 1986, 35 (4): 145-150
Pham-Tuan H, Kaskavelis L, Daykin C A, Janssen H G. Method development in high-performance liquid chromatography for high-throughput profiling and metabonomic studies of biofluid samples. Journal of Chromatography B, 2003, 789(2): 283-301
Poucke V C, Keyser D K, Baltusnikiene A, McEvoy J D G, Peteghem V C. Liquid chromatographic tandem spectrometric detection of banned antibacterial growth promoters in animal feed. Analytical Chimica Acta, 2003, 483: 99-109
Power S B, Donnelly W J, McLaughlin J G, Walsh M C, Dromey M F. Accidental carbadox overdosage in pigs in an Irish weaner-producing herd. Veterinary Record, 1989, 124(14): 367-370
Ramos D F J, Silveira D I N, Graaf D G. Column liquid chromatographic determination of carbadox and olaquindox in feeds. Journal of Chromatography, 1991, 558(1): 125-130
Rose M D, Bygrave J, Tarbin J A. Determination of quinoxaline carboxylic acid (metabolite of carbadox) in animal tissue by HPLC. Food Addition Contamination, 1995, 12(2): 177-183
Roybal J E, Munns R K, Shimoda W. Liquid chromatographic determination of carbadox residues in animal feed. Journal of AOAC international, 1985, 68(4): 653-657
Rutalj M, Bazulic D, Sapunar-Postruznik J. Quinoxaline-2-carboxylic acid (QCA) in swine liver and muscle. Food Additives and Contaminants, 1996, 13(8): 879-882
Scheutwinkel-Rrich M, VonDer H W. Sister-chromatid exchange in Chinese hamster V79 cells exposed to quindoxin, carbadox and olaquindox. Mutation Research, 1984, 139(4): 199-202
Sestakova I, Skarka P, Manousek 0, Determination of QCA in porcine liver by polar-graphic. Journal of Biological Chemistry, 1988,16(22): 29-32
Sin D W M, Chung L P K, Lai M M C, Siu S M P, Tang H P 0. Determination of quinoxaline-2-carboxylic acid, themajor metabolite of carbadox, in porcine liverbyisotope dilution gas chromatography-electron capturenegative ionization mass spectrometry. Analytical Chimica Acta, 2004, 508(2): 147-158
Slim R M, Robertson D G, Albassam M, Reily M D, Robosky L, Dethloff L A. Metabonomics, dietary influences and cultural differences: a ~1H NMR-based study of urine samples obtained from healthy British and Swedish subjects. Toxicology and Applied Pharmacology, 2002, 183(2): 108-109
Smith Lewis L. Key challenges for toxicologists in the 21st century. Trends in Pharmacological Sciences, 2001, 22(6): 281-285
Spierenburg T J, Lenthe V H, Graaf D G, Jager L P. Liquid chromatographic determination of olaquindox in medicated feeds and in contents of porcine gastrointestinal tract. Journal of AOAC international, 1988,71(6): 1 106-1 109
Sram R J, Salome F R, Jaroslava K. Dominant lethal mutation in female mice after oral administration of cyadox and olaquindox. Biologizace A Chemizace Zivocisne Vyroby Veterinaria, 1986, 22(1): 29-35
Stanley E G, Bailey N J, Bollard M E, Haselden J N, Waterfield C J, Holmes E, Nicholson J K. Sexual dimorphism in urinary metabolite profiles of Han Wistar rats revealed by nuclear-magnetic-resonance-based metabonomics. Analytical Biochemistry, 2005, 343(2): 195-202
Sugimoto M, Kikuchi S, AritaM, Soga T, Nishioka T, TomitaM. Large-scale prediction of cationic metabolite identity and migration time in capillary electrophoresis mass spectrometry using artificial neural networks. Analytical Chemistry, 2005, 77(1): 78-84
Sykora I, Marhan O, Gandalovicova D. Effects of the nonantibiotic growth stimulators carbdox and cyadox on reproduction in laboratory animals. Veterinarni Medicina, 1981, 26(6): 367-377
Tarra Fuchs, Kent S Gates, Jae-Taeg Hwang, Marc M. Greenberg Photosensitization of Guanine-Specific DNA Damage by a Cyano-Substituted Quinoxaline Di-N-oxide. Greenberg Chemical research toxicology, 1999, 12: 1 190-1 194
Taylor J, King R D, AltmannT, Fiehn O. Application of metabolomics to plant genotype discrimination using statistics and machine learning. Bioinformatics, 2002, 18: 241-248
Tennant R W. The National Center for Toxicogenomics: using new technologies to inform mechanistic toxicology. Environment Health Perspective, 2002, 110: 8-11
Thorpe V A. A collaborative study: high-pressure liquid chromatographic determination of carbadox and pyrantel tartrate in animal feeds. Journal of Chromatography Science, 1988, 26(11): 545-550
Thorpe V A. Rapid colorimetric method for carbadox in animal feeds. Journal of AOAC international, 1976, 59(6): 1 290-1 293
Tolstikov V V, Lommen A, Nakanishi K, Tanaka N, Fiehn O. Monolithic Silica-Based Capillary Reversed-Phase Liquid Chromatography/Electrospray Mass Spectrometry for Plant Metabolomics. Analytical Chemistry, 2003, 75(23): 6 737-6 740
Vanova L, Kolouch F, Sevcik B. The action of cyadox on rabbit reproduction. Biological Chemistry Zivocisne Vyroby-Veterinary, 1986, 22(1): 47-52
Voogd C E, Van D J J. The mutagenic action of quindoxin, carbadox, olaquindox and some other N-Oxide on bacteria and yeast. Mutation Research, 1980, 78(3): 233-242
Wu Y J, Wang Y L, Huang L L, Tao Y F, Yuan Z H, Chen D M. Simultaneous determination of five quinoxaline-1, 4-dioxides in animal feeds using ultrasonic solvent extraction and high-performance liquid chromatography. Analytical Chimica Acta, 2006, 569(1-2): 97-102
Yang J, Xu G W, Zheng Y F, Kong H W, Pang T, Lv S, Yang Q. Diagnosis of liver cancer using HPLC-based metabonomics avoiding false-positive resultfrom hepatitis and hepatocirrhosis diseases. Journal of Chromatography B, 2004, 813: 59-65
Yoshimura H, Nakmura M, Koeda T. Mutagenicities of carbadox and olaquindox growth promoters for pigs. Mutation Research, 1981, 90: 49-55