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.
| Snyderwine, E G; Kroll, R; Rubin, R J (1988) The possible role of the ethanol-inducible isozyme of cytochrome P450 in the metabolism and distribution of carbon disulfide. Toxicol Appl Pharmacol 93:11-21 |
