Xenobiotic Metabolism

异生物质代谢

• 批准号: 6672822
• 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/6672822
• 关键词: benzene; biotransformation; carcinogen testing; cyanides; cytochrome P450; detoxification; enzyme activity; genetically modified animals; heterocyclic compounds; high performance liquid chromatography; hydroxylation; laboratory mouse; laboratory rat; mass spectrometry; monoterpenes; nuclear magnetic resonance spectroscopy; phenols; quinoline; species difference; toxin metabolism; ultraviolet spectrometry; urinalysis; western blottings

Pulegone is a monoterpene found in the essential oil of several mints, including Pennyroyal. These mints are used in flavoring food and beverages. Pennyroyal and Pennyroyal oil have also been used as an abortifacient. The use of Pennyroyal oil, which contains about 85% pulegone, as an abortifacient has resulted in serious toxicity and death. Pulegone has been nominated to the NTP for toxicity and carcinogenicity studies. As part of those studies disposition studies in rats and mice are being conducted which have determined that pulegone is rapidly absorbed and excreted. At doses from 0.8 to 80 mg/kg, mice excrete about 80% of the dose in urine and 20% in feces in 24 hr. Rats eliminate about 50% in urine and 20% in feces in 24 hr. Tissue concentrations are thus lower in mice than rats. Male rats tend to have higher tissue concentrations, especially in kidney, than female rats but this sex difference is not seen in mice. The higher tissue concentrations in male rats are probably due to binding to alpha2u globulin. Chronic exposure to chemicals which bind to this protein often lead to kidney tumors in the male rat. Metabolism of pulegone in mice differs from rats in that several mercapturic acid and aromatic metabolites identified in rat urine are not present in mouse urine. This difference in metabolic profile could be due to the much more rapid biotransformation in mice leading to hydroxylation and conjugation of pulegone. This is a detoxification process. Mercapturic acids arise from reaction of GSH with alkylating agents. Formation of alkylating agents often correlates with toxicity. Thus, pulegone may be expected to be less toxic to mice than rats. Lidocaine and prilocaine are local anesthetics approved for use in humans. Lidocaine can be metabolized to 2,6-xylidine. Prilocaine can be metabolized to o-toluidine. Both 2,6-xylidine and o-toluidine have been shown to be rodent carcinogens; however the carcinogenic potential of the parent compounds have not been adequately investigated. Further, investigations into the genotoxicity of either lidocaine, prilocaine, 2,6-xylidine, or o-toluidine have been inconclusive in Samonella assays. The present work is an effort to better characterize the mutagenic potential of this class of anesthetics. Work in progress involves using the Ames mutagenicity test to detect possible compound-derived mutagenic metabolites excreted in urine. To date, male rats have been dosed by gavage with either lidocaine, prilocaine, 2,6-xylidine, and o-toluidine (all doses at 100 mg/kg, n=4 rats/treatment group). Urine from one animal from each group has been fractionated on HPLC for analysis in the Ames test. If mutagenicity is detected in any fraction, mutagenic metabolites will be isolated and characterized using LC/MS. Methods development with the Ames test is currently underway.

Pulegone是一种在包括Pennyroyal在内的几种薄荷的精油中发现的单二烯。这些薄荷器用于调味食品和饮料。 Pennyroyal和Pennyroyal油也已被用作流型剂。 pennyroyal油的使用含有大约85％的pulegone，作为流型牙，导致了严重的毒性和死亡。普列酮已被提名为NTP进行毒性和致癌性研究。作为这些研究的一部分，正在进行大鼠和小鼠的性格研究，这些研究确定了pulegone迅速吸收和排泄。在0.8至80 mg/kg的剂量下，小鼠在尿液中排出约80％的剂量，在24小时内排出20％的粪便。大鼠在24小时内消除了约50％的尿液和20％的粪便。因此，小鼠的组织浓度低于大鼠。雄性大鼠的组织浓度往往比雌性大鼠更高，尤其是在肾脏中，但在小鼠中没有看到这种性别差异。雄性大鼠的组织浓度较高可能是由于与α2U球蛋白的结合。长期暴露于与该蛋白质结合的化学物质中，通常会导致雄性大鼠的肾脏肿瘤。小鼠中pulegone的代谢与大鼠的不同，因为在大鼠尿液中鉴定出的几种胃酸和芳族代谢产物在小鼠尿液中不存在。代谢特征的这种差异可能是由于小鼠的生物转化更快，导致羟基化和偶联。这是一个排毒过程。胃酸是由GSH与烷基化剂的反应引起的。烷基化剂的形成通常与毒性相关。因此，pulegone可能比大鼠对小鼠的毒性更小。 利多卡因和prilocaine是被批准用于人类的局部麻醉药。利多卡因可以代谢为2,6-二甲苯胺。 prilocaine可以代谢为O-甲磺酸胺。 2,6-二甲苯和o-甲磺烷既已证明是啮齿动物的。但是，尚未对父母化合物的致癌潜力进行充分研究。此外，在萨莫尼拉分析中尚无定论，对利多卡因，丙型原因，2,6-二甲苯胺或O-甲磺酸胺的遗传毒性进行了研究。目前的工作是为了更好地表征这类麻醉药的诱变潜力。正在进行的工作涉及使用AMES诱变测试来检测尿液中排出的化合物衍生的诱变代谢产物。迄今为止，雄性大鼠已经用利多卡因，丙caine，2,6-二甲苯和O-甲硅苯胺剂量剂量（所有剂量以100 mg/kg的剂量，n = 4大鼠/治疗组）。来自每组的一只动物的尿液在HPLC上被分馏，以分析AMES测试。如果在任何馏分中都检测到诱变性，则使用LC/MS分离并表征诱变代谢物。 AMES测试的方法开发目前正在进行中。