Protective efficacy of various carbonyl compounds and their metabolites, and nutrients against acute toxicity of some cyanogens in rats: biochemical and physiological studies

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Cyanogens are widely used in industries and their toxicity is mainly due to cyanogenesis. The antidotes for cyanide are usually instituted for the management of cyanogen poisoning. The present study reports the protective efficacy of 14 carbonyl compounds and their metabolites, and nutrients (1.0 g/kg; oral; +5 min) against acute oral toxicity of acetonitrile (ATCN), acrylonitrile (ACN), malononitrile (MCN), propionitrile (PCN), sodium nitroprusside (SNP), succinonitrile (SCN), and potassium ferricyanide (PFCN) in rats. Maximum protection index was observed for alpha-ketoglutarate (A-KG) against MCN and PCN (5.60), followed by dihydroxyacetone (DHA) against MCN (2.79). Further, MCN (0.75 LD50) caused significant increase in cyanide concentration in brain, liver and kidney and inhibition of cytochrome c oxidase activity in brain and liver, which favorably responded to A-KG and DHA treatment. Up-regulation of inducible nitric oxide synthase by MCN, PCN and SNP, and uncoupling protein by PCN and SNP observed in the brain was abolished by A-KG administration. However, no DNA damage was detected in the brain. MCN and SNP significantly decreased the mean arterial pressure, heart rate, respiratory rate and neuromuscular transmission, which were resolved by A-KG. The study suggests a beneficial effect of A-KG in the treatment of acute cyanogen poisoning.

Abraham P, Lockwood A, Patka J, Rabinovich M, Sutherland J, Chester K. (2015). Sodium nitroprusside in intensive care medicine and issues of cyanide poisoning, cyanide poisoning prophylaxis, and thiocyanate poisoning. In: Toxicology of cyanides and cyanogens experimental, applied and clinical aspects (Alan H Hall, Gary E Isom, Gary A Rockwood eds), Wiley Blackwell, West Sussex, UK, 129–150.

Bhattacharya R. (2004). α-Ketoglutarate: a promising antidote to cyanide poisoning. In: Pharmacological Perspectives of Toxic Chemicals and their Antidotes (Flora SJS, Romano JA, Baskin SI, Sekhar K eds), Narosa Publishing House, New Delhi, India, 411–430.

Bhattacharya R. (2015). Recent perspectives on alpha-ketoglutarate. In: Toxicology of cyanides and cyanogens experimental, applied and clinical aspects (Alan H Hall, Gary E Isom, Gary A Rockwood eds), Wiley Blackwell, West Sussex, UK, 317–329.

Bhattacharya R, Flora SJS. (2009). Cyanide toxicity and its treatment In: Handbook of Toxicology of Chemical Warfare Agents (Gupta RC ed), New York, Elsevier, 255–270.

Bhattacharya R, Lakshmana Rao PV. (1997). Cyanide induced DNA fragmentation in mammalian cell cultures. Toxicology 123: 207–215.

Bhattacharya R, Rao P, Singh P, Yadav SK, Upadhyayay P, Malla S, Gujar NL, Lomash V, Pant SC. (2014). Biochemical, oxidative and histological changes caused by sub-acute oral exposure of some synthetic cyanogens in rats: Ameliorative effect of α-ketoglutarate. Food Chem Toxicol 67: 201–211.

Bhattacharya R, Satpute RM, Hariharakrishnan J, Tripathi H, Saxena, PB. (2009). Acute toxicity of some synthetic cyanogens in rats and their response to oral treatment with alpha-ketoglutarate. Food Chem Toxicol 47: 2314–2320.

Bhattacharya R, Tulsawani RK. (2008). In vitro and In vivo evaluation of various carbonyl compounds against cyanide toxicity with particular reference to alpha-ketoglutaric acid. Drug Chem Toxicol 31: 149–161.

Bhattacharya R, Vijayaraghavan R. (2002). Promising role of alpha-ketoglutarate in protecting against the lethal effects of cyanide. Hum Exp Toxicol 21: 297–303.

Borron SW. (2015). Cyanogenic aliphatic nitriles. In: Toxicology of cyanides and cyanogens experimental, applied and clinical aspects (Alan H. Hall, Gary E. Isom, Gary A. Rockwood, eds), Wiley Blackwell, West Sussex, UK, 166–180.

Chanas B, Wang H, Ghanayem BI. (2003). Differential metabolism of acrylonitrile to cyanide is responsible for the greater sensitivity of male vs. female mice: role of CYP2E1 and epoxide hydrolases. Toxicol Appl Pharmacol 193: 293–302.

Cooperstein SJ, Lazarow A. (1951). A microspectrophotometric method for the determination of cytochrome oxidase. J Biol Chem 189: 665–670.

Delhumeau G, Cruz-Mendoza AM, Lojero CG. (1994). Protection of cytochrome C oxidase against cyanide inhibition by pyruvate and α-ketoglutarate. Effect of aeration in vitro. Toxicol Appl Pharmacol 126: 345-351.

Dixon WJ. (1965). The up-and-down method for small samples. J Am Stat Assoc 60: 967–978.

Epstein J. (1947). Estimation of microquantities of cyanide. Anal Chem 19: 272–274.

Feldstein M, Klendshoj NC. (1954). The determination of cyanide in biologic fluids by microdiffusion analysis. J Lab Clin Med 44: 166–17.

Hadri L El, Chanas B, Ghanayem BI. (2005). Comparative metabolism of methacrylonitrile and acrylonitrile to cyanide using cytochrome p4502E1 and microsomal epoxide hydrolase-nullmice. Toxicol Appl Pharmacol 205: 116–125.

Hall AH, Dart R, Bogdan G. (2007). Sodium thiosulfate or hydroxocobalamin for the empiric treatment of cyanide poisoning? Ann Emerg Med 49: 806–813.

Hall VA, Guest JM. (1992). Sodium nitroprusside-induced cyanide intoxication and prevention with sodium thiosulfate prophylaxis. Am J Crit Care 1: 19–27.

Mirkin DB. (2015). The special case of acrylonitrile (CH2=CH-C≡N) In: Toxicology of cyanides and cyanogens experimental, applied and clinical aspects (Alan H Hall, Gary E Isom, Gary A Rockwood eds), Wiley Blackwell, West Sussex, UK, 181–194.

Niknahad H, Khan S, O’Brien P. (1995). Hepatocyte injury resulting from the inhibition of mitochondrial respiration at low oxygen concentrations involves reductive stress and oxygen activation. Chemico-Biol Inter 98: 27–44.

Niknahad H, Khan S, Sood C, O’ Brien PJ. (1994). Prevention of cyanide-induced cytotoxicity by nutrients in isolated rat hepatocytes. Toxicol Appl Pharmacol 128: 271-79.

Niknahad H, O’Brien PJ. (1996). Antidotal effect of dihydroxyacetone against cyanide toxicity in vivo. Toxicol Appl Pharmacol 138: 186–191.

Patnaik P. (2007). A Comprehensive Guide to the Hazardous Properties of Chemical Substances, 3rd Edn, John Wiley & Sons, Inc, NJ, USA.

Prabhakaran K, Li L, Borowitz JL, Isom GE. (2006). Inducible nitric oxide synthase up-regulation and mitochondrial glutathione depletion mediate cyanide-induced necrosis in mesencephalic cells. J Neurosci Res 84: 1003–1011.

Rao P, Singh P, Yadav SK, Gujar NL, Bhattacharya R. (2013). Acute toxicity of some synthetic cyanogens in rats: Time-dependent cyanide generation and cytochrome oxidase inhibition in soft tissues after sub-lethal oral intoxication. Food Chem Toxicol 59: 595–609.

Saillenfait AM, Sabate JP. (2000). Comparative developmental toxicities of aliphatic nitriles: in vivo and in vitro observations. Toxicol Appl Pharmacol 163: 149–163.

Sambrook J, Russell WD. (2000). Protocol: DNA isolation from mammalian tissue. In: Molecular Cloning: A Laboratory Manual (Sambrook J, Russel WD eds), Cold spring Harbor Laboratory Press, NY, 623–627.

Schwartz C, Morgan RL, Way LM, Way JL. (1979). Antagonism of cyanide intoxication with sodium pyruvate. Toxicol Appl Pharmacol 50: 437-441.

Scolnick B, Hamel D, Woolf AD. (1993). Successful treatment of life-threatening propionitrile exposure with sodium nitrite/sodium thiosulfate followed by hyperbaric oxygen. J Occup Med 35: 577–580.

Their R, Lewalter J, Bolt HM. (2000). Species difference in acrylonitrile metabolism and toxicity between experimental animals and human based on observations in human accidental poisoning. Arch Toxicol 74: 184–189.

Tulsawani R, Kumar D, Bhattacharya R. (2007). Effect of pre-treatment of α-ketoglutarate on cyanide-induced toxicity and alterations in various physiological variables in rodents. Biomed Environ Sci 20: 56–63.

Vesey CJ, Cole PV. (1985). Blood cyanide and thiocyanate concentrations produced by long-term therapy with sodium nitroprusside. Br J Anaes 57: 148–155.

Wu Jong –C, Hseu You –C, Chen Chin –H, Wang Shu –H, Chen Ssu –C. (2009). Comparative investigations of genotoxic activity of five nitriles in the comet assay and the Ames test. J Hazard Mater 169: 492–497.

Zhang X, Li L, Prabhakaran K, Zhang L, Leavesley HB, Borowitz JL, Isom GE. (2007). Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARα activation and oxidative stress. Toxicol Appl Pharmacol 223: 10–19.

Interdisciplinary Toxicology

The Journal of Institute of Experimental Pharmacology of Slovak Academy of Sciences

Journal Information

CiteScore 2017: 2.36

SCImago Journal Rank (SJR) 2017: 0.580
Source Normalized Impact per Paper (SNIP) 2017: 1.134


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