XENOBIOTIC METABOLISM

异生代谢

• 批准号: 6106564
• 负责人: Leo T Burka
• 金额: --
• 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/6106564
• 关键词: biotransformation; detoxification; gender difference; herbicides; laboratory mouse; laboratory rat; laxative; pharmacokinetics; phenols; species difference; toxicology; toxin metabolism

5-(Hydroxymethyl)furfural (HMF) arises from acid-catalyzed thermal degradation of hexoses during cooking. There are reports which indicate that HMF can be converted in vitro to a strong mutagen by sulfation of the alcohol functionality and reports that HMF may initiate and promote colonic aberrant crypt foci in rats. Based primarily on these two observations, the NTP has initiated toxicology studies on HMF. As part of this study we have conducted studies of 14C-HMF metabolism and disposition in mice and rats. The emphasis of these studies was to determine if any evidence could be found for in vivo formation of the proposed mutagenic sulfate conjugate. The disposition studies indicate that HMF is rapidly absorbed with no accumulation in tissues. The majority of the radioactivity is eliminated in urine in both mice and rats. Three major urinary metabolites have been isolated and identified. None of the metabolites were the proposed sulfate conjugate and none of them require the intermediacy of the proposed reactive sulfate conjugate. As another measure of reactive intermediates formed from HMF, the amount of unextractable radioactivity associated with protein was determined in selected tissues (protein covalent binding). In general, the amount of unextractable radioactivity was a few tenths of a nmol of HMF equivalents/mg protein. Thus, there is some evidence that reactive intermediates are formed from metabolism of HMF, but at a relatively low rate. o-, m-, and p-Nitrotoluenes are used in the production of dyes, rubber, and agricultural chemicals. Toxicology studies of these chemicals have clearly shown that in F344 rats o-nitrotoluene is the most toxic isomer. All three nitrotoluenes are initially metabolized to the corresponding nitrobenzyl alcohols followed either by further oxidation, or conjugation with small polar endogenous entities such as glucuronic acid or sulfate. An unexplored pathway possibly responsible for the toxicity of o-nitrotoluene is an intramolecular reaction between the o-nitro group and the benzylic carbon bearing a leaving group such as sulfate to give either increased alkylating ability or a reactive metabolite. o- and p-nitrobenzyl p-toluenesulfonates, model compounds for the corresponding sulfates, were prepared and hydrolyzed in CH3CN-H2O. There was little difference in rate of hydrolysis of the two isomers indicating that the difference in toxicity is probably not due to a difference in alkylating ability of a similar metabolite in vivo. p-Toluenesulfonic acid and p-nitrobenzyl alcohol were obtained from p-nitrobenzyl tosylate, as expected. However, hydrolysis of o-nitrobenzyl tosylate gave not only p-toluenesulfonic acid and o-nitrobenzyl alcohol, but also a third product identified as o-nitrosobenzaldehyde. Studies are ongoing to explore biological significance of this observation.

5-（羟甲基）呋喃（HMF）来自 烹饪过程中己糖的六糖热降解。 有报告表明HMF可以转换为 通过酒精功能的硫酸化，体外对强诱变剂 并报道HMF可能会发起和促进结肠异常 大鼠的地下室焦点。主要基于这两个观察结果 NTP启动了有关HMF的毒理学研究。作为这项研究的一部分 我们已经对14C-HMF代谢和 小鼠和大鼠的性格。这些研究的重点是 确定是否可以找到任何证据表明体内形成 提出的诱变硫酸盐结合物。处置研究 表明HMF迅速吸收，没有积聚 组织。大部分放射性在尿液中消除 小鼠和老鼠。三个主要的泌尿代谢物是 孤立和确定。没有代谢物是提出的 硫酸盐结合物，它们都不需要 提出的反应性硫酸盐结合物。作为反应性的另一种量度 由HMF形成的中间体，不可提取的数量 在选定中确定与蛋白质相关的放射性 组织（蛋白质共价结合）。通常， 不可提取的放射性是十分之一的NMOL HMF 等效物/mg蛋白。因此，有一些证据表明反应性 中间体由HMF的代谢形成，但在 相对较低的速率。在 染料，橡胶和农业化学品的生产。毒理学 这些化学物质的研究清楚地表明，在F344大鼠中 O-亚硝基苯甲苯是最有毒的异构体。这三个亚硝基苯甲酸均为 最初代谢与相应的硝基苯醇 然后进一步氧化，或与小的结合 极性内源性实体，例如葡萄糖酸或硫酸盐。一个 未开发的途径可能导致 O-硝基苯二烯是O-硝基之间的分子内反应 集团和苯二碳带有一个离开组的含量 硫酸盐具有提高的烷基化能力或活性 代谢物。 O-和P-硝基苯基P-二甲苯磺酸盐，模型 制备相应硫酸盐的化合物，并 在CH3CN-H2O中水解。速率几乎没有差异 两个异构体的水解表明 毒性可能不是由于A的烷基化能力差异 类似的代谢物在体内。 p-二甲苯磺酸和P-硝基苯基 如预期的那样，从硝基苯基甲苯甲酯获得酒精。 然而，O-亚硝基苯甲酸的水解不仅给出 P-二甲苯磺酸和O-硝基苯基醇，但也是第三个 产品被识别为O-亚硝基亚苯甲醛。研究正在进行 探索该观察结果的生物学意义。