Xenobiotic Metabolism

异生物质代谢

• 批准号: 7593859
• 负责人: Leo T Burka
• 金额: $ 95.2万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593859
• 关键词: 1-Propanol; Acetone; Acetylcysteine; Acids; Adhesives; Air; Amines; Animals; Biological Factors; Carboxylic Acids; Chemicals; Class; Cytochrome P450; Deamination; Dose; Drug toxicity; Epichlorohydrin; Epoxy Compounds; Epoxy Resins; Erythrocytes; Feces; Furans; Furosemide; Glucuronides; Glutathione; Glutathione S-Transferase; Goals; Health; Hepatic; Human; Hydroxy Acids; In Vitro; Inorganic Sulfates; Isopropanol; Keto Acids; Label; Light; Metabolism; Microsomes; Mono-S; Mus; N-acetylserine; NMR Spectroscopy; National Toxicology Program; Object Attachment; Oral; Parents; Pharmaceutical Preparations; Phenols; Plant Resins; Positioning Attribute; Production; Property; Rattus; Reaction; Reporting; Rest; SK-Furosemide; Signal Transduction; System; Tissues; Toxic effect; Unspecified or Sulfate Ion Sulfates; Urine; Work; Xenobiotic Metabolism; adduct; base; carbonyl group; carcinogenicity; design; dimethyldioxirane; experience; furan; glucuronide; glycidyl ethers; interest; ipomeanine; ipomeanol; metabolic abnormality assessment; n-butoxyethanol; n-butyl glycidyl ether; oxidation; uptake; urinary

The majority of our work in the past year has concerned the disposition and metabolism of n-butyl glycidyl ether (BGE). BGE is a high production chemical used primarily in epoxy-based resins and adhesives. While the most common epoxy resins are composed of bis-phenol A and epichlorohydrin, they may contain other phenols or epoxides to modify their properties. BGE is being studied by the National Toxicology Program as an example of the aliphatic glycidyl ether class of epoxy components. The disposition of 14C-labeled BGE, was studied in rats and mice. The majority of a single oral dose (2-200 mg/kg) was excreted in urine (rats, 84-92%; mice, 64-73%) within 24 h. The rest of the dose was excreted in feces (rats, 2.6-7.7%; mice 5.3-12%) and in expired air as 14CO2 (rats, 1.5%; mice 10-18%), or remained in the tissues (rats, 2.7-4.4%; mice, 1.5-1.7%). No parent BGE was detected in rat or mouse urine. Fifteen urinary metabolites were identified, including 3-butoxy-2-hydroxy-1-propanol and its mono-sulfate or mono-glucuronide conjugates, 3-butoxy-2-hydroxypropionic acid, O-butyl-N-acetylserine, butoxyacetic acid, 2-butoxyethanol, and 3-butoxy-1-(N-acetylcystein-S-yl)-2-propanol, the mercapturic acid metabolite derived from conjugation of GSH with BGE at the C-1 position. Some of these metabolites underwent further ω-1 oxidation to form a 3-hydroxybutoxy substitution. One urinary metabolite was from ω-oxidation of 3-butoxy-1-(N-acetylcystein-S-yl)-2-propanol to yield the corresponding carboxylic acid. Oxidative deamination of 3-butoxy-1-(cystein-S-yl)-2-propanol gave the corresponding α-keto acid and α-hydroxy acid metabolites that were present in mouse urine but not in rat urine. An in vitro incubation of BGE with GSH showed that the conjugation occurred only at the C-1 position with or without the addition of glutathione S-transferase. Butoxyacetic acid, one of the BGE metabolites, is considered to be responsible for the erythrotoxicity of butoxyethanol. There was neither evidence of enhanced uptake of 14C by erythrocytes, nor any evidence of erythrotoxicity from the BGE-treated animals. We have had a long-term interest in the metabolism of furans. This 5-membered heterocycle is found in natural products and is generally considered a structural alert for toxicity. Furans are metabolized by cytochromes P450 either to an epoxide or to a ring-opened intermediate consisting of two carbonyl groups substituted on either end of a vinyl group (O=C-C=C-C=O, dioxabutene). We reported the in vitro metabolism of 4-ipomeanol and ipomeanine, furan-containing natural products, last year. By using d6-dimethyldioxirane in d6-acetone the dioxabutene intermediate could be detected by NMR spectroscopy. In vitro oxidation with hepatic microsomes in the presence of glutathione led to adducts in which as many as 3 new bonds were formed between the reactive intermediate and GSH. In light of the toxicity generally observed with furans, we were curious about the lack of toxicity associated with furosemide (Lasix). This furan-containing drug has been in use for decades with few problems. Metabolism studies to date have offered few clues for the lack of toxicity. Our experience with dimethyldioxirane oxidation of other furans led us to try oxidizing furosemide in the d6-dimethyldoxirane/acetone system. The NMR spectrum of the reaction product contained no signals attributable to the dioxabutene, instead the first observable signals were from a product of the secondary amine in furosemide and the dioxabutene. This intramolecular reaction is fast allowing no build-up of the reactive intermediate. This likely is the explanation for the lack of toxicity of the drug. Thus ends our study of furan metabolism and ES0210-75: xenobiotic Metabolism.

在过去的一年中，我们的大部分工作都涉及N-丁基糖基乙醚（BGE）的性格和代谢。 BGE是一种主要用于环氧树脂树脂和粘合剂的高生产化学物质。 虽然最常见的环氧树脂由双酚A和环氯二醇组成，但它们可能含有其他苯酚或环氧化物来修饰其性质。 国家毒理学计划正在研究BGE，以脂肪族糖基醚类别的环氧树脂成分的一个例子。 在大鼠和小鼠中研究了14C标记的BGE的处置。 在24小时内，大多数单一口服剂量（2-200 mg/kg）在尿液中排出（大鼠，84-92％；小鼠，64-73％）。其余剂量在粪便中排出（大鼠，2.6-7.7％；小鼠5.3-12％），在过期的空气中排出AS 14CO2（大鼠，1.5％；小鼠10-18％），或保留在组织中（大鼠，2.7-4.4％；小鼠；小鼠，1.5-1-1.7％）。 在大鼠或小鼠尿液中未检测到父母BGE。 鉴定了15个尿代谢产物，包括3-丁克西-2-羟基-1-丙醇及其单硫酸盐或单硫酸盐或单葡萄糖醛酸糖苷二轭物，3-丁氧基-2-羟基氧基丙酸，o-butylyl-n-乙酰基乙酸酯，丁基乙酰甲酯3-丁克西-1-（N-乙酰基半基）-2-丙醇，硫酸代谢物是由GSH与BGE在C-1位置的结合而得出的。 这些代谢产物中的一些经过了进一步的ω-1氧化，形成了3-羟基丁氧基的取代。 一种泌尿代谢物是来自3-丁克西-1-（N-乙酰基囊菌S-基）-2-丙醇的ω-氧化，以产生相应的羧酸。 3-丁克氧-1-（Cystein-Syl）-2-丙醇的氧化脱氨酸给出了相应的α-酮酸和小鼠尿液中存在但不存在于大鼠尿液中的α-羟基酸代谢物。 BGE与GSH的体外孵育表明，这种结合仅在添加谷胱甘肽S-转移酶的情况下仅在C-1位置发生。 丁氧乙酸是BGE代谢产物之一，被认为是丁氧乙醇的红细胞毒性的原因。既没有证据表明红细胞增强了14C的吸收，也没有任何证据表明经过BGE处理的动物的红细胞毒性。 我们对弗拉斯的代谢有长期的兴趣。 这种5元的杂环在天然产物中发现，通常被认为是毒性的结构警报。 通过细胞色素P450代谢为环氧化物，或者是由在乙烯基基团任一端取代的两个羰基组成的环的中间体（O = C-C = C-C = O，二木丁烯）。 我们报道了去年4-二氨基酚和伊米氨醇的体外代谢，含有Furan的天然产物。 通过在D6-丙酮中使用d6-二甲基二氧烷烷，可以通过NMR光谱检测到二羟丁烯中间体。 在存在谷胱甘肽的情况下，用肝微粒体的体外氧化导致加合物，其中反应性中间体和GSH之间形成了多达3个新键。 鉴于通常用呋喃观察到的毒性，我们对与速尿相关的缺乏毒性（LASIX）感到好奇。 这种含Furan的药物已经使用了数十年，几乎没有问题。 迄今为止，新陈代谢研究提供了缺乏毒性的线索。 我们在其他呋喃的二甲基二氧化烷氧化方面的经验使我们尝试在D6-二甲基氧化烷/丙酮系统中尝试氧化速尿。 反应产物的NMR光谱不含dioxabutene归因的信号，而是第一个可观察到的信号来自速尿和二氧化苯胺中的二次胺的产物。 这种分子内反应很快，不允许反应性中间体积聚。 这可能是对药物缺乏毒性的解释。 因此，我们对Furan代谢和ES0210-75的研究结束了：异种生物代谢。

项目成果

Mouse bone marrow micronucleus test results do not predict the germ cell mutagenicity of N-hydroxymethylacrylamide in the mouse dominant lethal assay.

小鼠骨髓微核测试结果不能预测小鼠显性致死试验中 N-羟甲基丙烯酰胺的生殖细胞致突变性。

• DOI: 10.1002/em.10139
• 发表时间: 2003
• 期刊: Environmental and molecular mutagenesis
• 影响因子: 2.8
• 作者: Witt,KristineL;Hughes,LoriA;Burka,LeoT;McFee,AlfredF;Mathews,JamesM;Black,SherryL;Bishop,JackB
• 通讯作者: Bishop,JackB

Disposition of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5h)-furanone (mx) in b6c3f1 mice and f344 rats.

3-氯-4-(二氯甲基)-5-羟基-2(5h)-呋喃酮 (mx) 在 b6c3f1 小鼠和 f344 大鼠中的处置。

• DOI: 10.1080/00984100290071522
• 发表时间: 2002
• 期刊: Journal of toxicology and environmental health. Part A
• 作者: Lebetkin,EdwardH;Chen,Ling-Jen;Burka,LeoT
• 通讯作者: Burka,LeoT

Mercury concentrations in brain and kidney following ethylmercury, methylmercury and Thimerosal administration to neonatal mice.

• DOI: 10.1016/j.toxlet.2004.07.014
• 发表时间: 2004-12
• 期刊: Toxicology letters
• 影响因子: 3.5
• 作者: G. Harry;M. Harris;L. T. Burka

Metabolism and disposition of 1-bromopropane in rats and mice following inhalation or intravenous administration.

• DOI: 10.1016/j.taap.2006.01.010
• 发表时间: 2006-08
• 期刊: Toxicology and applied pharmacology
• 影响因子: 3.8
• 作者: C. Garner;S. Sumner;J. Davis;J. Burgess;Y. Yueh;J. Demeter;Q. Zhan;J. Valentine;A. Jeffcoat;L. T. Burka;J. Mathews

NTP technical report on the toxicity studies of Butanal oxime (CAS No. 110-69-0) administered in drinking water and by gavage to F344/N rats and B6C3F1 mice.

NTP 关于丁醛肟（CAS 号 110-69-0）通过饮用水和强饲法对 F344/N 大鼠和 B6C3F1 小鼠进行毒性研究的技术报告。

• 发表时间: 2004
• 期刊: Toxicity report series
• 作者: Burka,LeoT