Biological Markers of Acute Acrylonitrile Intoxication in Rats as a Function of Dose and Time

Benz, Frederick W.; Nerland, Donald E.; Corbett, Donna; LI, JUNYU

doi:10.1093/toxsci/36.2.141

Cited by 9 publications

(32 citation statements)

References 16 publications

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“…Blood was collected in a heparinized syringe by cardiac puncture. Approximately 1 ml of whole blood was immediately mixed with 20 l of 0.125 M sodium nitrite and frozen in liquid N 2 (Benz et al, 1997). Liver, kidneys, brain, and lungs were excised, rinsed in ice-cold phosphate-buffered saline (pH 7.4), and frozen in liquid N 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Cyanide concentrations in blood and tissue homogenates were determined by a modified spectrophotometric method (Baselt, 1988;Benz et al, 1997). Specimens (200 -300 mg) of kidney, lung, or liver were homogenized in cold 0.1 M sodium phosphate buffer (pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

“…Cyanide is converted to thiocyanate via rhodanese and eliminated in the urine. Both AN and CEO react with tissue thiols, leading to rapid depletion of GSH (Farooqui and Ahmed, 1983;Ghanayem et al, 1985;Benz et al, 1997;Nerland et al, 2001). CEO was shown to react with DNA and is mutagenic, which suggested that CEO may be responsible for the carcinogenic effects of AN (Guengerich et al, 1981).…”

Section: Acrylonitrile (Anmentioning

confidence: 99%

Section: Acrylonitrile (Anmentioning

confidence: 99%

“…The primary target of acute toxicity of AN is the central nervous system due, at least partially, to the liberation of cyanide (Ahmed and Patel, 1981;Benz et al, 1997). Cyanide-like symptoms are observed in animals after administration of AN (Graham, 1965;Ahmed and Patel, 1981), and cyanide antidotal regimens have been used in the United States to counter the acute toxicity of this chemical in humans (Benz et al, 1997). High doses of N-acetylcysteine are recommended in Germany for the treatment of acute AN poisoning in humans (Buchter et al, 1984), and sulfur-containing compounds were used to suppress AN metabolism and toxicity in animals (Benz et al, 1990).…”

Section: Acrylonitrile (Anmentioning

confidence: 99%

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Cytochrome P450 2E1 (CYP2E1) is Essential for Acrylonitrile Metabolism to Cyanide: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

Wang

Chanas²,

Ghanayem³

2002

Drug Metabolism and Disposition

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ABSTRACT:Acrylonitrile (AN) is a rodent carcinogen and suspected human carcinogen. Metabolism of AN proceeds via conjugation with glutathione or epoxidation via cytochrome P4502E1 (CYP2E1) to cyanoethylene oxide (CEO). It was hypothesized that CEO metabolism via epoxide hydrolase (EH) is the primary pathway for cyanide formation. The objective of this work is to assess the enzymatic basis of metabolism to cyanide. Male wild-type and CYP2E1-null mice received 0, 2.5, 10, 20, or 40 mg of AN/kg by gavage, and cyanide was measured in blood and tissues. CYP2E1 and EH expression were assessed using Western blot analyses. Present results demonstrated that cyanide concentrations in blood and tissues of AN-treated wild-type mice were higher at 1 versus 3 h, increased in a dose-dependent manner, and were significantly higher in AN-treated versus vehicle-treated mice. In contrast, cyanide concentrations in the blood and tissues of AN-treated CYP2E1-null mice were not statistically different from those of vehicle-treated mice. Furthermore, this work showed that EH is expressed in CYP2E1-null and wild-type mice. In conclusion, under the current experimental conditions using CYP2E1-null mice, current work demonstrated for the first time that CYP2E1-mediated oxidation is a prerequisite for AN metabolism to cyanide. Since earlier studies showed that CYP2E1 is the only enzyme responsible for AN epoxidation, it is concluded that AN metabolism to CEO is a prerequisite for cyanide formation, and this pathway is exclusively catalyzed by CYP2E1. Finally, this work confirmed that cyanide plays an essential role in the causation of the acute toxicity/mortality of AN.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Acrylonitrile (Anmentioning

confidence: 99%

Section: Acrylonitrile (Anmentioning

confidence: 99%

Section: Acrylonitrile (Anmentioning

confidence: 99%

See 3 more Smart Citations

Cytochrome P450 2E1 (CYP2E1) is Essential for Acrylonitrile Metabolism to Cyanide: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

Wang

Chanas²,

Ghanayem³

2002

Drug Metabolism and Disposition

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Zinc, Copper, Iron, and Selenium Levels in Brain and Liver of Mice Exposed to Acrylonitrile

Wang

Xing

et al. 2009

Biol Trace Elem Res

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The mechanism of toxicity of acrylonitrile (AN) has not been fully defined. The research described herein was undertaken to investigate the possible effects of AN on the levels of metallic elements in liver and brain of mice. Thirty-two mice were randomly assigned to four separate groups and treated intraperitoneal (i.p.) once daily for 1 week. Mice in the control group received normal saline, and mice in the three exposure groups received 5, 10, or 20 mg AN/kg b.w. Samples of brain and liver were collected immediately after decapitation. Tissue levels of trace elements (zinc, copper, iron) were determined with flame atomic absorption spectrophotometer or double channel atomic fluorescence absorption spectrophotometer (selenium). Mean brain weights of AN-treated mice were increased as a function of dose compared to controls, but there was no significant change in the ratio of liver/body weight in the four groups. While mean brain zinc decreased as a function of AN dosage, mean liver zinc of the low-dose group significantly increased (p < 0.05); mean liver copper in the medium-dose AN group was significantly higher compared to controls (p < 0.05); however, mean brain copper was increased, but the difference did not attain statistical significance in the three AN groups when compared with the controls (p > 0.05). Mean brain iron levels were significantly decreased in the middle-dose AN group (p < 0.05), but there were no consistent changes in liver iron. Tissue levels of selenium in brain and liver were similar for the control and AN treatment groups. AN induces significant and differential changes in the levels of zinc, copper, and iron in brain and liver. These changes likely play a pivotal role in mediating AN toxicity, most likely via changes in cellular redox status.

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

Campian

Benz

2008

Toxicology

Self Cite

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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.

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Biological Markers of Acute Acrylonitrile Intoxication in Rats as a Function of Dose and Time

Cited by 9 publications

References 16 publications

Cytochrome P450 2E1 (CYP2E1) is Essential for Acrylonitrile Metabolism to Cyanide: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

Cytochrome P450 2E1 (CYP2E1) is Essential for Acrylonitrile Metabolism to Cyanide: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

Zinc, Copper, Iron, and Selenium Levels in Brain and Liver of Mice Exposed to Acrylonitrile

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

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