CYSTEINE CONJUGATE SULFOXIDATION BY MULTIPLE FMOS

多个 FMOS 对半胱氨酸缀合物磺化

• 批准号: 2905460
• 负责人: Adnan A. Elfarra
• 金额: $ 16.49万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2905460
• 关键词: acetylcysteine; acyltransferase; animal tissue; chemical carcinogen; chemical conjugate; cysteine; environmental toxicology; enzyme substrate; enzyme substrate analog; flavins; gender difference; histopathology; isozymes; kidney function; laboratory rat; liver function; methionine; oxygenases; renal toxin; selenomethionine; species difference; sulfoxide; toxicant interaction; toxin metabolism

DESCRIPTION: (Adapted from the Investigator's Abstract) Many chemicals and their corresponding cysteine S-conjugates, which are intermediates in the mercapturic acid pathway, are metabolized in vivo to cysteine S-conjugate sulfoxides and/or N-acetylcysteine S-conjugate sulfoxides. Previous work in this laboratory provided the first evidence for the involvement of flavin-containing monooxygenases (FMOs) in cysteine conjugate S-oxidase activities of rat and rabbit liver and kidney. Sulfoxidation of the cysteine S-conjugates of the industrial solvents trichloroethylene and tetrachloroethylene has also been shown to yield electrophilic sulfoxides that may contribute to the nephrotoxicity and carcinogenicity of these chemicals. Because there are currently five known FMO isoforms (identified as FMO1-5) and some of these isoforms exhibit gender- and tissue- dependent expression, the broad objective of the proposed is to characterize the relative contributions of FMO isoforms in the metabolism and toxicity of cysteine S-conjugates. Similar studies will be conducted with methionine and selenomethionine, structural analogues of cysteine S-conjugates which we have also identified as FMO substrates and are known to cause toxicity when given to animals at high levels. Specific experimental objectives are: 1) To isolate and characterize the substrate selectivities of rat hepatic and renal FMO3 and FMO4; 2) To characterize species-, gender-, and age-dependent expression of FMO4, and provide further characterization of FMO1 and FMO3 expression in liver and kidney; 3) To quantitate in vivo FMO activity in rats and mice using cysteine S-conjugates; 4) To characterize the toxicity associated with cysteine S-conjugate sulfoxides and selenomethionine oxide. The proposed studies will allow for a better understanding of FMO expression and the mechanisms of toxicity of cysteine S-conjugates and related chemical, leading to a more accurate assessment of human risk to these chemicals.

描述：（改编自研究者摘要）许多化学品和 它们相应的半胱氨酸S-缀合物，它们是中间体 硫醇尿酸途径，在体内代谢为半胱氨酸 S-缀合物 亚砜和/或N-乙酰半胱氨酸S-缀合物亚砜。 之前的工作于 该实验室提供了第一个参与的证据 半胱氨酸结合 S-氧化酶中的含黄素单加氧酶 (FMO) 大鼠和兔肝脏和肾脏的活性。 磺化氧化 工业溶剂三氯乙烯和半胱氨酸 S-结合物 四氯乙烯也被证明可以产生亲电子亚砜 可能会导致这些物质的肾毒性和致癌性 化学品。 因为目前已知的 FMO 亚型有五种（已鉴定为 如 FMO1-5），其中一些亚型表现出性别和组织依赖性 表达式，提议的广泛目标是描述 FMO亚型在代谢和毒性中的相对贡献 半胱氨酸 S-缀合物。 类似的研究将用蛋氨酸进行 和硒代蛋氨酸，半胱氨酸 S-缀合物的结构类似物，我们 也被确定为 FMO 底物，并且已知在以下情况下会引起毒性： 以高水平给予动物。 具体实验目标是：1） 分离和表征大鼠肝脏和 肾 FMO3 和 FMO4； 2) 表征物种、性别和年龄依赖性 FMO4 的表达，并提供 FMO1 和 FMO3 的进一步表征 在肝脏和肾脏中表达； 3) 定量体内 FMO 活性 使用半胱氨酸 S-缀合物的大鼠和小鼠； 4）表征毒性 与半胱氨酸 S-缀合物亚砜和硒代蛋氨酸氧化物相关。 拟议的研究将有助于更好地理解 FMO 表达 半胱氨酸S-缀合物的毒性机制及相关 化学物质，从而更准确地评估人类对这些物质的风险 化学品。