CS2: TOXIC INTERACTIONS OF ALCOHOLS AND KETONES

CS2：醇和酮的毒性相互作用

• 批准号: 3250154
• 负责人: ROBERT J. RUBIN
• 金额: $ 14.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-03-01 至 1988-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3250154
• 关键词: acetone; alanine transaminase; carbon; carbon tetrachloride; cytochrome P450; cytotoxicity; enzyme induction /repression; ethanol; industry; ketones; necrosis; neurochemistry; norepinephrine; occupational hazard; solvents; toxicant interaction; toxin metabolism; unspecific monooxygenase

Although there is considerable amount of information concerning the toxicity of individual chemicals, there is a paucity of information concerning the toxicity associated with exposure to multiple agents. This is particularly true of the potential interaction of diverse toxic agents with ethanol, a widely used and often abused chemical agent, particularly among industrial workers. This project proposes to investigate the interaction of ethanol, other alcohols, and other industrial solvents (ketones) on metabolism, distribution, excretion, and toxicity of carbon disulfide (CS2). In recent years CS2 has been shown to be metabolized by an hepatic mixed function oxidase (MFO) system to carbonyl sulfide (COS), giving rise to electrophilic products such as atomic sulfur and presumably an oxygen-containing reactive intermediate of CS2. Induction of the enzyme system leads to an enhanced elimination of CS2 and thus, presumably, to a decreased neurotoxic hazard. But this occurs at the cost of increased hepatotoxicity due to the elevated liberation of highly reactive intermediates directly in the liver. Ethanol, as well as several other alcohols, are well known to be both substrates as well as inducers of the MFO system. In fact, there has been considerable evidence for the interaction of a variety of alcohols with both CCl4 and CHCl3 hepatotoxicity, both halocarbons also requiring metabolic activation by the MFO system for expression of their toxicity. A number of aliphatic and aromatic ketones are also known to enhance halocarbon toxicity. In this proposal the kinetics of CS2 metabolism in isolated hepatic microsomes will be studied following in vivo and in vitro exposures to the test agents. This will be done to determine if these chemicals can, under acute conditions, serve as alternate substrates for the MFO system and thus inhibit the metabolism of CS2, and under delayed conditions induce the enzyme system, thereby enhancing CS2 metabolism. These experiments will be substantiated by studying the effect of treatment on CS2 metabolism in vivo. The distribution of CS2 will be determined as will the exhalation of COS and CO2. Several indices of hepatic and neurotoxicity will also be evaluated. These include (1) liver histology for evidence of hepatic necrosis, (2) serum glutamic-pyruvic transaminase, (3) hepatic cytochrome P450 levels, (4) hepatic P450-dependent nitro-anisole demethylase and aniline hydroxylase and (5) brain norepinephrine as a measure of neurochemical toxicity.

尽管有相当多的信息涉及 个别化学品的毒性，信息匮乏 关于与接触多种药剂相关的毒性。 这 对于不同有毒物质的潜在相互作用尤其如此 乙醇是一种广泛使用且经常被滥用的化学试剂，特别是 产业工人之中。 本项目建议调查 乙醇、其他醇和其他工业溶剂的相互作用 （酮）对碳的代谢、分布、排泄和毒性的影响 二硫化物（CS2）。 近年来，CS2已被证明可通过以下途径代谢： 肝脏混合功能氧化酶（MFO）系统转化为羰基硫（COS）， 产生亲电子产物，例如原子硫，并且可能 CS2的含氧反应中间体。 酶的诱导 系统导致 CS2 的增强消除，因此，大概， 减少神经毒性危险。 但这的代价是增加 由于高活性物质的释放增加而导致肝毒性 中间体直接进入肝脏。 乙醇以及其他几种 众所周知，醇既是该酶的底物，又是该酶的诱导剂。 MFO系统。 事实上，已有大量证据表明 多种醇与 CCl4 和 CHCl3 的相互作用 肝毒性，这两种卤代烃也需要通过代谢激活 MFO系统表达了其毒性。 一些脂肪族和 芳香酮也已知会增强卤化碳的毒性。 在这个 提出离体肝微粒体中 CS2 代谢动力学 在体内和体外暴露于测试剂后进行研究。 这样做是为了确定这些化学物质是否可以在急性 条件下，作为 MFO 系统的替代基材，从而 抑制 CS2 的代谢，并在延迟条件下诱导 酶系统，从而增强CS2代谢。 这些实验将 通过研究治疗对 CS2 代谢的影响得到证实 体内。 CS2 的分布将被确定，呼出也将被确定 COS 和 CO2。 一些肝脏和神经毒性指标也将被 评价。 这些包括 (1) 肝脏组织学，以获取肝脏疾病的证据 坏死，(2) 血清谷氨酸-丙酮酸转氨酶，(3) 肝细胞色素 P450 水平，(4) 肝 P450 依赖性硝基苯甲醚脱甲基酶和 苯胺羟化酶和（5）脑去甲肾上腺素作为衡量 神经化学毒性。