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; 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

在啮齿动物中使用的苯甲胺蛋白（PT）最近被鉴定为一种多物质致癌物，但是尚不清楚负责致癌性的分子物种。最近报道了PT，羟基苯胺（PT-CAT）的儿茶酚代谢产物，可能是负责PT至少部分毒性/致癌性的分子物种。例如，由喹酮与喹酮一起氧化还原循环的氧化还原循环呈现了潜在的癌变机制。然而，儿茶酚结构还使PT-CAT成为无处不在的酶Catechol-O-甲基转移酶（COMT）的潜在底物，该酶使许多分子的潜在反应性儿茶酚代谢物失活，包括激素雌二醇的分子。我们假设PT-CAT可以抑制儿茶酚-O-甲基转移酶（COMT），从而在易感组织中通过PT-CAT本身或内源性儿茶酚雌激素（CES）增强遗传毒性。进行了研究，以确定PT处理和PT-CAT本身对体外和体内4-羟基雌二醇和2-羟基雌二醇的COMT介导的分解代谢的影响。用PT（50 mg/kg/d）处理雌性小鼠21天，然后处死。暴露7天，尿液高原的PT-CAT浓度。体外实验表明，PT治疗导致游离CE的增加，通常通过COMT清除，并且COMT的肝儿茶酚清除能力同时降低。在体外，PT-CAT是COMT的底物，具有内源性底物测量的范围内的动力学特性。 PT-CAT是具有90-300 nm IC50的Catechol雌激素O-甲基化的极有效的混合型抑制剂。 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饮用水的氯化，尤其是水含有腐殖质的地方。据估计，MX在某些饮用水中占诱变活性的50％。最近在大鼠的生物测定法显示肿瘤发生率增加，主要是在肝脏和甲状腺中。在小鼠中进行的NTP研究正在进行中，以补充大鼠研究。在支持本研究的小鼠中，正在进行MX的分布/代谢研究。口服服用时，MX在小鼠中迅速吸收，并在尿液中排泄为几种极性代谢物。组织/血比是最高的内置内科（> 100），腺体胃，肠和肾脏。与口服剂量相比，静脉内给药会导致血液中较高，长期的放射性水平。 MX处置似乎由其化学反应性主导，在给药部位发现了最高浓度的放射性。 -F344大鼠，B6C3F1小鼠，异生物代谢，苯甲胺胺，MX