Age-related changes in toxicity and biotransformation of potassium cyanide in male C57BL/6N mice.
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.
McMahon
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Experimental Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Birnbaum
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LS
D000375:Aging; D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000254:growth & development*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology*; D008930:Mitochondria, Liver / Q000201:enzymology*; D011190:Potassium Cyanide / Q000378:metabolism / Q000633:toxicity*; D012016:Reference Values; D013466:Sulfurtransferases / Q000378:metabolism; D013884:Thiosulfate Sulfurtransferase / Q000378:metabolism
D003576:Electron Transport Complex IV; D013466:Sulfurtransferases; D013884:Thiosulfate Sulfurtransferase; C021550:3-mercaptopyruvate sulphurtransferase; D011190:Potassium Cyanide