The acute lethality of acrylonitrile is not due to brain metabolic arrest

Abstract

Acrylonitrile (AN) is an organic compound produced in large quantities by the chemical industry and is acutely toxic. One mechanism proposed to explain the toxicity of AN is metabolism by P450 into cyanide (CN). Although blood and brain levels of CN in rats following an LD90 dose of AN are consistent with acute toxicity, blocking CN formation with P450 inhibitors does not prevent lethality. Another mechanism implicated in toxicity is covalent binding of AN to cysteine residues in tissue proteins. Previous work in our laboratory has shown that AN can irreversibly inactivate the catalytically active cysteine-149 in glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Inactivation of GAPDH by AN would be expected to impair glycolytic ATP production and, when coupled to the inhibition of mitochondrial ATP synthesis by the AN metabolite CN, would result in metabolic arrest, particularly in brain. In this study we have measured the high energy metabolites Phosphocreatine (PCr), ATP, ADP and AMP by HPLC and compared their levels in the brains of rats treated with an LD90 dose of AN, when respiration ceased, vs. controls. Two methods of rapid brain freezing in liquid nitrogen were used: Funnel Freezing (FF) and Head Immersion (HI). AN administration resulted in large decreases in PCr of 74% (FF) and 80% (HI) but relatively minor decreases in ATP of 5% (FF) and 21% (HI) and Energy Charge of 6% (FF) and 10% (HI). Thus, although substantial depletion of PCr was observed, possibly due to inhibition of creatine kinase by AN, we found no evidence that brain ATP is depleted when respiration ceases in AN-intoxicated rats.

Hepatoprotective activity of quercetin against acrylonitrile‐induced hepatotoxicity in rats

“…Chronic exposure of rats to ACN has been reported to produce a dose‐related increase in glial cell tumors (astrocytomas) 7. Moreover, previous studies have shown that ACN exposure was associated with induction of oxidative stress (OS) and reduction in tissue content of cysteine 8, lysine, methionine, and GSH as well as disturbance of pyruvate metabolism 9. Furthermore, increased lipid peroxidation, oxidative damage (OD) of DNA, and deficiency of antioxidant protection in rat brain were reported following ACN chronic exposure 10.…”

Acrylonitrile induction of rodent neoplasia: Potential mechanism of action and relevance to humans

“…While mitochondrial damage was described in vitro after long-term acrylonitrile administration, 95,96 no ATP depletion was observed in the brain tissues of male SD rats exposed to a single subcutaneous injection of a LD 90 dose (115 mg/kg) of acrylonitrile, suggesting that other mechanisms also may be involved in the acute toxicity of this compound. 97…”

“…While mitochondrial damage was described in vitro after long-term acrylonitrile administration, 95,96 no ATP depletion was observed in the brain tissues of male SD rats exposed to a single subcutaneous injection of a LD 90 dose (115 mg/kg) of acrylonitrile, suggesting that other mechanisms also may be involved in the acute toxicity of this compound. 97 Depletion of GSH is likely to exacerbate toxicity of acrylonitrile. Thus, a single subcutaneous dose of acrylonitrile administered to male SD rats at 30 or 50 mg/kg body weight produced focal erosions of glandular stomach mucosa, which became more severe with time and were associated with hepatic and gastric glutathione depletion (25% decrease in liver and 50% decrease in glandular stomach).…”

Cytotoxic effects of acrylonitrile on human umbilical cord mesenchymal stem cells in vitro

“…These results indicate that ACN may destroy the hematopoietic microenvironment. It has been reported that ACN was extremely reactive with rat tissue proteins in vivo (23). Blood was the most reactive tissue studied and hemoglobin was the most reactive protein in blood.…”