FMOs: Roles in Metabolism and Toxicity

FMO：在代谢和毒性中的作用

• 批准号: 7322518
• 负责人: Adnan A. Elfarra
• 金额: $ 23.8万
• 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 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322518
• 关键词: Active Sites; Animal Feed; Animals; Antioxidants; Biochemical; Cells; Chemicals; Complementary DNA; Cystathionine; Cysteine; Depressed mood; Environmental Pollution; Enzymes; Exhibits; Exposure to; FMO1; FMO2; FMO3; FMO4; Family; Female; Fishes; Gel; Goals; Growth; Hepatic; Hepatocyte; Hepatotoxicity; Homocysteine; Homocystine; Homocystinuria; Human; In Vitro; Inborn Genetic Diseases; Infant; Kidney; Laboratories; Leukotriene E4; Liver; Mammalian Cell; Mediating; Messenger RNA; Metabolism; Methionine; Methods; Modeling; Mus; Mutate; Mutation; Nephrotoxic; Neurologic; Nitrogen; Numbers; Odors; Pathway interactions; Pharmaceutical Preparations; Physiological; Play; Predisposition; Property; Protein Isoforms; Proteins; Race; Rattus; Reaction; Recombinants; Research; Research Personnel; Risk Assessment; Rodent; Role; S-(1,2,2-trichlorovinyl)-L-cysteine; Selenium; Selenomethionine; Solvents; Substrate Specificity; Sulfur; Sulfur Compounds; Syndrome; Tetrachloroethylene; Tissues; Total Parenteral Nutrition; Toxic effect; Trichloroethylene; Work; age related; base; chemical property; detoxication; dietary constituent; exposed human population; flavin-containing monooxygenase; human tissue; in vivo; male; methionine sulfoxide; nephrotoxicity; oxidation; programs; research study; sex; toxicant; trimethylamine

DESCRIPTION (provided by applicant): The long-term objective of this research is to characterize the roles of flavin-containing monooxygenases (FMOs) in the metabolism and toxicity of various drugs, toxicants, endogenous compounds, and their major metabolites. The FMO family is comprised of at least five isoforms, which catalyze oxidation of compounds containing N-, S-, and Se-atoms. With most chemicals, the FMO-mediated reaction is a detoxication reaction. However, with compounds such as selenomethionine, a naturally occurring compound that has antioxidant and anticancer properties, and the cysteine S-conjugates of the environmental contaminants trichloroethylene and tetrachloroethylene, the FMO-mediated pathway is a bioactivation reaction. Another known FMO substrate, methionine, has been implicated in toxicity in humans with inborn errors of homocysteine metabolism (homocystinuria) and in infants receiving total parenteral nutrition. Additionally, genetic defects in FMO3 have been associated with the inability to metabolize the dietary constituent trimethylamine, a situation that causes "fish-odor syndrome". Thus, examination of FMO expression in animal and human tissues, the substrate specificities of the various FMOs, and the biochemical and toxic effects of the FMO-derived metabolites will allow for a more accurate, mechanism-based assessment of risk associated with human exposure to these chemicals. It will also guide the search for safer drugs and chemicals. In this application, the hypothesis that FMOs play important roles in metabolism and toxicity of cysteine S-conjugates, selenomethionine, and methionine will be examined. Experiments using both rodent and human cells and/or tissues in vitro and in rodents in vivo will be carried out. We will develop immunochemical and functional probes to provide further characterization of rodent and human FMOs. A major focus of this project is on FMO4, whose expression has not been clearly characterized at the native protein level in any species. The specific aims are to: 1) develop immunochemical and 2D gel electrophoretic methods to characterize rat and human FMOs; 2) purify and characterize FMO4 from rat kidney; 3) characterize the roles of FMOs in metabolism of potential substrates; 4) characterize the role of FMOs in the metabolism and toxicity of methionine and selenomethionine; and 5) further investigate the role of FMOs in the metabolism and toxicity of the cysteine S-conjugate of trichloroethylene.

描述（由申请人提供）：这项研究的长期目的是表征含黄素单加氧酶（FMO）在各种药物，毒物，内源性化合物及其主要代谢物的代谢和毒性中的作用。 FMO家族至少由五种同工型组成，这些同工型催化含有N-，S-和Se-Atoms的化合物的氧化。使用大多数化学物质，FMO介导的反应是解毒反应。然而，使用硒甲氨酸等化合物，一种具有抗氧化剂和抗癌特性的天然化合物，以及环境污染物的三氯乙烯和四氯乙烯的半胱氨酸S-偶联物，FMO介导的途径是生物活化反应。另一个已知的FMO底物蛋氨酸与人类同型半胱氨酸代谢（同卵巢尿症）和接受肠胃外营养的婴儿的毒性有关。另外，FMO3中的遗传缺陷与无法代谢饮食组成型三甲胺有关，这种情况会导致“鱼类杜尔综合征”。因此，检查动物和人体组织中FMO表达，各种FMO的底物特异性以及FMO衍生代谢产物的生化和毒性作用将允许对与人类接触这些化学物质相关的风险进行更准确，基于机制的评估。它还将指导寻找更安全的药物和化学物质。在此应用中，将研究FMO在新陈代谢和毒性中起重要作用的假说，将检查半胱氨酸S-偶联物，硒蛋氨酸和蛋氨酸的毒性。将在体外和体内使用啮齿动物和/或组织使用啮齿动物和/或组织进行实验。我们将开发免疫化学和功能探针，以提供啮齿动物和人类FMO的进一步表征。该项目的主要重点是FMO4，其表达在任何物种中尚未在天然蛋白质水平上的表达。具体目的是：1）开发免疫化学和2D凝胶电泳方法来表征大鼠和人类FMO； 2）从大鼠肾脏中纯化和表征FMO4； 3）表征FMO在潜在底物代谢中的作用； 4）表征FMO在蛋氨酸和硒蛋氨酸的代谢和毒性中的作用； 5）进一步研究了FMO在三氯乙烯半胱氨酸S-偶联物的代谢和毒性中的作用。

项目成果

Renal and hepatic toxicity of trichloroethylene and its glutathione-derived metabolites in rats and mice: sex-, species-, and tissue-dependent differences.

三氯乙烯及其谷胱甘肽衍生代谢物对大鼠和小鼠的肾和肝毒性：性别、物种和组织依赖性差异。

• 发表时间: 2001
• 期刊: The Journal of pharmacology and experimental therapeutics.
• 作者: Lash,LH;Qian,W;Putt,DA;Hueni,SE;Elfarra,AA;Krause,RJ;Parker,JC
• 通讯作者: Parker,JC

Human kidney flavin-containing monooxygenases and their potential roles in cysteine s-conjugate metabolism and nephrotoxicity.

人肾含黄素单加氧酶及其在半胱氨酸 s-缀合物代谢和肾毒性中的潜在作用。

• DOI: 10.1124/jpet.102.042911
• 发表时间: 2003
• 期刊: The Journal of pharmacology and experimental therapeutics.
• 作者: Krause,ReneeJ;Lash,LawrenceH;Elfarra,AdnanA
• 通讯作者: Elfarra,AdnanA

Cytotoxicity of the novel glutathione-activated thiopurine prodrugs cis-AVTP [cis-6-(2-acetylvinylthio)purine] and trans-AVTG [trans-6-(2-acetylvinylthio)guanine] results from the National Cancer Institute's anticancer drug screen.

新型谷胱甘肽激活的硫代嘌呤前药顺式 AVTP [顺式 6-(2-乙酰乙烯基硫基)嘌呤] 和反式 AVTG [反式-6-(2-乙酰乙烯基硫基)鸟嘌呤] 的细胞毒性来自美国国家癌症研究所的抗癌药物筛选。

• DOI: 10.1124/dmd.32.3.321
• 发表时间: 2004
• 期刊: Drug metabolism and disposition: the biological fate of chemicals
• 作者: Gunnarsdottir,Sjofn;Elfarra,AdnanA
• 通讯作者: Elfarra,AdnanA

Renal toxicity of perchloroethylene and S-(1,2,2-trichlorovinyl)glutathione in rats and mice: sex- and species-dependent differences.

• DOI: 10.1006/taap.2001.9358
• 发表时间: 2002-03
• 期刊: Toxicology and applied pharmacology
• 影响因子: 3.8
• 作者: L. Lash;W. Qian;D. Putt;S. Hueni;A. Elfarra;A. R. Sicuri;J. Parker

Effects of pH, temperature, and chemical structure on the stability of S-(purin-6-yl)-L-cysteine: evidence for a novel molecular rearrangement mechanism to yield N-(purin-6-yl)-L-cysteine.

pH、温度和化学结构对 S-(purin-6-yl)-L-半胱氨酸稳定性的影响：产生 N-(purin-6-yl)-L-半胱氨酸的新型分子重排机制的证据。

• DOI: 10.1021/tx9501905
• 发表时间: 1996
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Elfarra,AA;Hwang,IY
• 通讯作者: Hwang,IY