RENAL TOXICITY OF CARBON DISULFIDE

二硫化碳的肾毒性

• 批准号: 3250151
• 负责人: ROBERT J. RUBIN
• 金额: $ 17.57万
• 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 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3250151
• 关键词: acetone; alanine transaminase; carbon; carbon tetrachloride; cytochrome P450; cytotoxicity; diabetic acidosis; drug administration routes; electron microscopy; enzyme induction /repression; ethanol; glomerular filtration; hamsters; hepatotoxin; industry; inhalation drug administration; injection /infusion; ketones; laboratory mouse; laboratory rat; necrosis; neurochemistry; norepinephrine; occupational hazard; renal toxin; renal tubular transport; solvents; toxicant interaction; toxin metabolism; urea

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.

尽管有相当数量的关于 关于个别化学品的毒性，信息很少 关于暴露在多种制剂中的毒性。这 对于不同毒物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，尤其是 在产业工人中。该项目建议调查 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已被证明是由 一种肝脏混合功能氧化酶(MFO)系统与硫化碳酰(COS)的结合， 产生亲电产物，如原子硫和可能的 CS2的一种含氧的活性中间体。酶的诱导 系统导致了CS2的增强消除，并因此可能导致 降低了神经毒性危害。但这是以增加 高活性物质释放增多所致的肝毒性 直接进入肝脏的中间体。乙醇，以及其他几种 众所周知，醇既是底物也是诱导剂 MFO系统。事实上，已经有相当多的证据表明 多种醇与CCl4和CHCl3的相互作用 肝毒性，这两种卤素也需要代谢激活 MFO系统用于表达其毒性。一些脂肪族和 众所周知，芳香酮还会增强卤代烃的毒性。在这 建议在分离的肝微粒体中CS2代谢动力学 在体内和体外暴露于测试试剂后进行研究。 这样做是为了确定这些化学物质在急性中毒情况下是否可以 条件，作为MFO系统的替代基质，因此 抑制CS2的代谢，并在延迟条件下诱导 酶系统，从而促进CS2代谢。这些实验将是 通过研究治疗对大鼠CS2代谢的影响而得到证实 活着。CS2的分布将被确定，呼气将被确定 COS和二氧化碳。肝脏和神经毒性的几个指标也将是 已评估。这些包括(1)肝组织学证据。 (2)血清谷丙转氨酶，(3)肝细胞色素 P450水平，(4)肝脏P450依赖的硝基苯甲醚去甲基酶和 苯胺羟基酶和(5)脑去甲肾上腺素作为衡量 神经化学毒性。