HEPATOTOXICITY OF ATRAZINE AND ITS DEGRADATION PRODUCTS

阿特拉津及其降解产物的肝毒性

• 批准号: 7561479
• 负责人: YIMING LIU
• 金额: $ 12.49万
• 依托单位: JACKSON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561479
• 关键词: Atrazine; Biological; Biological Assay; Biological Markers; Computer Retrieval of Information on Scientific Projects Database; Computing Methodologies; Funding; Grant; Hepatotoxicity; Herbicides; Hour; In Vitro; Institution; Iron; Knowledge; Lipid Peroxidation; Liver Microsomes; Methanol; Methods; NADP; Oxidative Stress; Parents; Peer Review; Phase; Publications; Rattus; Relative (related person); Research; Research Personnel; Resources; Solutions; Source; Structure-Activity Relationship; System; Time; Toxic effect; Trichloroacetic Acid; United States National Institutes of Health; deethylatrazine; metabolic abnormality assessment

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Atrazine is one of the herbicides that are most heavily used in the world. The proposed research is focused on studying the hepatotoxicity of atrazine and its degradation products. In the funding period from 6/06 to 5/07, we studied the metabolism of atrazine in rat liver microsome with or without the presence of iron (III) by using an advantageous HPLC-ESI-MS/MS method. After incubation for 12 hours, metabolites were extracted by trichloroacetic acid + 50% methanol. Four phase I metabolites, i.e. deethylatrazine, deisopropylatrazine, hydroxyatrazine, and deisopropylhydroxyatrazine were always detected no matter Fe(III) presented or not. The concentrations of deethylatrazine and deisopropylatrazine were approx. 50-times higher than those of hydroxyatrazine and deisopropylhydroxyatrazine. In the presence of Fe(III), another metabolite, i.e. didealkylatrazine was identified in the incubation solutions. The concentration of didealkylatrazine was found to increase with the increase in Fe(III) concentration. To the best of our knowledge, this was the first study of atrazine degradation products in this biological in vitro system. In addition, we developed an HPLC-MS/MS method for the determination of 4-hydroxy-nonenal (4-HNE), a specific biomarker for lipid peroxidation. The method was highly selective and very sensitive with an LOD of 10 ng /mL 4-HNE in rat liver microsome incubation solution. Three peer-reviewed publications from this group are acknowledging the RCMI grant (12RR13459) in this funding period. Next year, we plan to study the effects of the identified degradation products of atrazine on NADPH induced lipid peroxidation in rat liver microsome, and compare the results with those from atrazine, thus obtaining the relative toxicity of the degradation products against their parent compound, atrazine. Both TBAS assay and the advantageous HPLC-MS/MS assay for 4-HNE will be used to assess the oxidative stress status. In addition, the potential structure-activity relationship (SAR) will be explored using computational methods including the semi empirical AM1.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 阿特拉津是世界上使用最多的除草剂之一。本论文主要研究阿特拉津及其降解产物的肝毒性。在6/06至5/07的资助期内，我们通过使用有利的HPLC-ESI-MS/MS方法研究了阿特拉津在有或没有铁（III）存在的大鼠肝微粒体中的代谢。孵育12小时后，用三氯乙酸+50%甲醇提取代谢物。无论Fe（III）存在与否，均能检测到去乙基阿特拉津、去异丙基阿特拉津、羟基阿特拉津和去异丙基羟基阿特拉津四种I相代谢物。脱乙基莠去津和脱异丙基莠去津的浓度约为0.001 mg/L。50-比羟基阿特拉津和去异丙基羟基阿特拉津高10倍。在存在Fe（III）的情况下，在孵育溶液中鉴别出另一种代谢产物，即二脱烷基莠去津。发现二脱烷基莠去津的浓度随着Fe（III）浓度的增加而增加。据我们所知，这是阿特拉津降解产物在这种生物体外系统的第一次研究。此外，我们开发了一种HPLC-MS/MS方法，用于测定脂质过氧化的特异性生物标志物4-羟基-壬烯醛（4-HNE）。该方法选择性好，灵敏度高，检出限为10 ng /mL。来自该小组的三篇同行评审出版物在此资助期内确认了RCMI赠款（12 RR 13459）。 明年，我们计划研究阿特拉津降解产物对NADPH诱导的大鼠肝微粒体脂质过氧化的影响，并与阿特拉津的结果进行比较，从而获得降解产物对其母体化合物阿特拉津的相对毒性。TBAS试验和4-HNE的有利HPLC-MS/MS试验均将用于评估氧化应激状态。此外，潜在的结构活性关系（SAR）将使用计算方法，包括半经验AM 1探索。