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Age-related changes in toxicity and biotransformation of potassium cyanide in male C57BL/6N mice
1Experimental Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Abstract:
Age-related changes in toxicity and biotransformation of KCN, an ubiquitous environmental toxicant, have not been previously examined. Male C57BL/6N mice aged 2-3 (young), 10-12 (middle-aged), and 25-30 (old) months were administered KCN at 1, 2, 4, and 6 mg/kg po, and toxic manifestations were monitored for up to 2 hr. The toxic response to KCN (prostration and labored breathing) was significantly greater in 10-12 and 25-30 month vs that in 2-3 month mice at 4 and 6 mg/kg KCN. The basis for this age-related difference in in vivo toxicity was examined by studying biotransformation of KCN to thiocyanate by liver and brain rhodanese (RHO), as well as activity of liver and brain cytochrome oxidase (C-OX), inhibition of C-OX by KCN, and activity of beta-mercaptopyruvate transsulfurase (MT). Tissue and blood levels of CN- following a toxic dose of 6 mg/kg KCN were also measured. No age-related differences were observed in the specific activity of liver and brain RHO, MT, or C-OX. In addition, no differences were observed in the percentage inhibition of C-OX by KCN, or in the Ki for inhibition of brain and liver C-OX. However, activity of brain RHO on a per gram tissue basis was significantly lower in 10-12 and 25-30 months vs that in 2-3 month mice. Liver and blood concentrations of CN- were not significantly different in 2-3 vs 10-12 month mice following treatment with 6 mg/kg KCN; however, significantly greater concentrations of CN- were observed at 4 and 25 min in brains of 10-12 month mice compared to that in 2-3 month mice. These results indicate that increased sensitivity to KCN in older mice may be due in part to a decrease in the amount of brain RHO and altered tissue kinetics of CN- following a toxic dose in older mice.
Insights
Older mice exhibit increased sensitivity to potassium cyanide (KCN) toxicity. This heightened susceptibility is linked to reduced brain rhodanese (RHO) activity and altered cyanide (CN-) kinetics in aged C57BL/6N mice.
Area of Science:
- Toxicology
- Environmental Health
- Aging Research
Background:
- Potassium cyanide (KCN) is an environmental toxicant with largely unexamined age-related toxicity.
- Understanding how aging affects KCN biotransformation and toxicity is crucial for public health.
Purpose of the Study:
- To investigate age-related differences in KCN toxicity and biotransformation in male C57BL/6N mice.
- To elucidate the underlying mechanisms of increased KCN sensitivity in older animals.
Main Methods:
- Mice of three age groups (young, middle-aged, old) were administered varying doses of KCN.
- Toxic responses, enzyme activities (rhodanese, cytochrome oxidase, beta-mercaptopyruvate transsulfurase), and cyanide levels were measured.
- Inhibition kinetics of cytochrome oxidase by KCN were analyzed.
Main Results:
- Older mice (10-12 and 25-30 months) showed significantly greater toxic responses to KCN compared to young mice (2-3 months).
- No age-related differences were found in liver/brain rhodanese, cytochrome oxidase, or beta-mercaptopyruvate transsulfurase specific activities, nor in cytochrome oxidase inhibition.
- Brain rhodanese activity per gram of tissue was significantly lower in older mice, and brain cyanide concentrations were higher post-KCN administration.
Conclusions:
- Increased KCN sensitivity in older mice is partly attributed to reduced brain rhodanese activity.
- Altered tissue kinetics of cyanide in the brain contribute to the observed age-related toxicity of KCN.