XENOBIOTIC METABOLISM

异生代谢

• 批准号: 6289881
• 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/6289881
• 关键词: biotransformation; detoxification; gender difference; herbicides; laboratory mouse; laboratory rat; laxative; pharmacokinetics; phenols; species difference; toxicology; toxin metabolism

Phenolphthalein (PT), used in over-the-counter laxatives, was recently been identified as a multisite carcinogen in rodents, but the molecular species responsible for the carcinogenicity is not known. A catechol metabolite of PT, hydroxyphenolphthalein (PT-CAT), was recently reported and may be the molecular species responsible for at least part of the toxicity/carcinogenicity of PT. For example, formation of free radicals as a result of redox cycling of PT-CAT semiquinone with the quinone present a potential carcinogenesis mechanism. However, the catechol structure also makes PT-CAT a potential substrate of the ubiquitous enzyme catechol-O-methyltransferase (COMT), which inactivates potentially reactive catechol metabolites of a number of molecules, including those of the hormone estradiol. We hypothesized that PT-CAT may inhibit the enzyme catechol-O-methyltransferase (COMT) and therefore potentiate genotoxicity by either PT-CAT itself or the endogenous catechol estrogens (CEs) in susceptible tissues. Studies were conducted to determine the effects of PT treatment and PT-CAT itself on the COMT-mediated catabolism of 4- and 2-hydroxyestradiol both in vitro and in vivo. Female mice were treated with PT (50 mg/kg/d) for 21 days and then sacrificed. PT-CAT concentration in urine plateaus by 7 days of exposure. In vitro experiments demonstrated that PT treatment resulted in an increase in free CEs, which are normally cleared by COMT and a concurrent decrease in the capacity of hepatic catechol clearance by COMT. In vitro, PT-CAT was a substrate of COMT, with kinetic properties within the range measured with endogenous substrates. PT-CAT was an extremely potent mixed-type inhibitor of the O-methylation of the catechol estrogens, with 90-300 nM IC50s. The above data, when taken together, suggest that chronic administration of PT may enhance metabolic redox cycling of both PT-CAT and the catechol estrogens and this, in turn, may contribute to PT-induced tumorigenesis.3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is a potent mutagen formed as a by-product of chlorination of drinking water, particularly where the water contains humic matter. MX has been estimated to account for 50% of the mutagenic activity in some drinking water. A recent bioassay in rats demonstrated an increased tumor incidence, primarily in liver and thyroid. An NTP study in mice is underway to complement the rat study. A distribution/metabolism study of MX in mice is being conducted in support of this study. MX is rapidly absorbed in mice when administered orally and is excreted in urine and feces as several polar metabolites. Tissue/blood ratios are highest inforestomach (>100), glandular stomach, intestine, and kidney, in that order. Intravenous administration results in high, prolonged levels of radioactivity in blood compared to oral dosing. MX disposition appears to be dominated by its chemical reactivity with highest concentrations of radioactivity being found at the site of administration. - F344 rats, B6C3f1 mice, xenobiotic metabolism, Phenolphthalein, MX

用于非处方泻药的酚酞 (PT) 最近被确定为啮齿类动物的多部位致癌物，但导致致癌性的分子种类尚不清楚。最近报道了 PT 的儿茶酚代谢物羟基酚酞 (PT-CAT)，它可能是至少部分 PT 毒性/致癌性的分子种类。例如，由于 PT-CAT 半醌与醌的氧化还原循环而形成自由基，这是一种潜在的致癌机制。然而，儿茶酚结构也使 PT-CAT 成为普遍存在的儿茶酚-O-甲基转移酶 (COMT) 的潜在底物，该酶可使许多分子的潜在反应性儿茶酚代谢物失活，包括激素雌二醇的代谢物。我们假设 PT-CAT 可能抑制儿茶酚-O-甲基转移酶 (COMT)，因此在易感组织中增强 PT-CAT 本身或内源性儿茶酚雌激素 (CE) 的遗传毒性。进行研究以确定 PT 治疗和 PT-CAT 本身对体外和体内 COMT 介导的 4- 和 2-羟基雌二醇分解代谢的影响。雌性小鼠接受 PT (50 mg/kg/d) 治疗 21 天，然后处死。暴露 7 天后尿液中 PT-CAT 浓度达到平台状态。体外实验表明，PT 治疗导致游离 CE 增加（通常由 COMT 清除），同时 COMT 清除肝儿茶酚的能力降低。在体外，PT-CAT 是 COMT 的底物，其动力学特性在内源性底物测量的范围内。 PT-CAT 是一种极其有效的儿茶酚雌激素 O-甲基化混合型抑制剂，IC50 为 90-300 nM。上述数据综合起来表明，长期给予 PT 可能会增强 PT-CAT 和儿茶酚雌激素的代谢氧化还原循环，而这反过来可能会促进 PT 诱导的肿瘤发生。 3-Chloro-4-(二氯甲基) )-5-羟基-2(5H)-呋喃酮 (MX) 是一种强效诱变剂，是饮用水氯化的副产品，特别是在水中含有腐殖质的情况下。据估计，MX 占某些饮用水中 50% 的诱变活性。最近对大鼠进行的一项生物测定表明肿瘤发病率增加，主要是肝脏和甲状腺。一项针对小鼠的 NTP 研究正在进行中，以补充大鼠研究。为了支持这项研究，正在进行小鼠体内 MX 的分布/代谢研究。 MX 口服后很快被小鼠吸收，并以几种极性代谢物的形式从尿液和粪便中排出。组织/血液比率最高的是胃（>100）、腺胃、肠和肾，依次排列。与口服给药相比，静脉给药会导致血液中放射性水平升高且持续时间较长。 MX 的处置似乎主要取决于其化学反应性，在给药部位发现了最高浓度的放射性。 - F344 大鼠、B6C3f1 小鼠、异生物质代谢、酚酞、MX