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Studies on the mechanism of acute toxicity of nitriles in mice
Abstract:
Acute toxicity and metabolism of 21 nitriles in mice were studied in relation to their chemical structures. All the test nitriles liberated cyanide ions both in vivo and in vitro, with the exception of benzonitrile , although the extent of liberation and the effect of carbon tetrachloride (CCl4) pretreatment on the mortality of animals differed among nitriles. From these results, test compounds were tentatively divided into three groups. In group 1 (13 compounds), acute toxicity was greatly reduced by CCl4 pretreatment, in group 2 (seven compounds), toxicity was not significantly changed or was somewhat enhanced, and in group 3, benzonitrile only, toxicity was clearly enhanced. The amount of cyanide was higher (0.68-0.80 microgram CN/g brain) at death in the brains of mice given group-1 compounds, the level being comparable to that found in mice killed by dosing with potassium cyanide. After oral doses of each nitrile, the time course for cyanide levels in the liver varied among the compounds. The difference between group-1 and -2 compounds lay in the dose-cyanide liberation relationship in liver, and in the kinetics for cyanide liberation in the hepatic microsomal enzyme system. Double-reciprocal plots of enzyme activity showed a linear relationship for nitriles of group 1 and a non-linear one for group 2. The relationship between log (1/LD50) and log P for the compounds in group 1 fitted a parabolic plot, while that for compounds in group 2 was linear.
Insights
Acute toxicity of nitriles in mice depends on cyanide liberation. Carbon tetrachloride pretreatment significantly reduced toxicity for most nitriles, indicating varied metabolic pathways and detoxification mechanisms.
Area of Science:
- Toxicology
- Biochemistry
- Pharmacology
Background:
- Nitriles are a class of organic compounds with diverse applications.
- Understanding their toxicity and metabolic fate is crucial for safety assessments.
- Cyanide liberation is a known mechanism of nitrile toxicity.
Purpose of the Study:
- To investigate the acute toxicity and metabolism of 21 nitriles in mice.
- To correlate toxicity with chemical structure and cyanide liberation.
- To evaluate the effect of carbon tetrachloride (CCl4) pretreatment on nitrile toxicity.
Main Methods:
- Acute toxicity testing in mice.
- In vivo and in vitro cyanide liberation assays.
- Effect of CCl4 pretreatment on mortality.
- Analysis of cyanide levels in brain and liver.
- Kinetic studies of hepatic microsomal enzyme systems.
- Quantitative structure-activity relationship (QSAR) analysis using log P and LD50.
Main Results:
- All tested nitriles, except benzonitrile, liberated cyanide in vivo and in vitro.
- CCl4 pretreatment reduced toxicity for 13 nitriles (Group 1), had no significant effect or enhanced toxicity for 7 nitriles (Group 2), and enhanced toxicity for benzonitrile (Group 3).
- Higher brain cyanide levels at death were observed in Group 1.
- Differences in dose-cyanide liberation relationship in the liver and kinetics in hepatic microsomal enzymes distinguished Group 1 and Group 2 compounds.
- Enzyme kinetics showed linear double-reciprocal plots for Group 1 and non-linear for Group 2.
- QSAR analysis revealed a parabolic relationship between log (1/LD50) and log P for Group 1, and a linear relationship for Group 2.
Conclusions:
- Nitrile toxicity is primarily mediated by cyanide liberation.
- Metabolic pathways and detoxification mechanisms differ among nitriles, influencing their toxicity.
- CCl4 pretreatment can be a useful tool to probe these metabolic differences.
- Chemical structure and lipophilicity (log P) are important determinants of nitrile toxicity and metabolism.