Friday, October 15, 2004

Biochemical basis for poisoning

The toxic effect of cyanide is ascribed predominantly to the production of anoxia following inhibition of cytochrome oxidase, a terminal mitochondrial respiratory chain enzyme. This enzyme contains two heme A and two copper ions. Cyanide has a special affinity for the heme ion and the reaction of cyanide with the multimeric iron enzyme complex is facilitated by first penetration of cyanide to protein crevices, with initial binding of cyanide to the protein followed by binding of cyanide to heme ion. Thereby, a cyanide-heme cytochrome oxidase complex is formed which renders the enzyme incapable of utilizing the oxygen. The resultant oxygen saturation of the blood imparts a cherry red color, which aids the diagnoses in most instances of cyanide poisoning. Inhibition of cytochrome oxidase results in interruption of electron transport chain and the oxidative phosphorylation. Resultant anaerobic metabolism with severely decreased ATP generation and concomitant increase in lactic acid production eventually leads to tissue hypoxia and metabolic acidosis. The inhibitory properties of cyanide may be ascribed to its ability to complex with metals. Besides, iron containing cytochrome oxidase, there are other metallo-enzymes containing molybdenum, zinc or copper which are equally sensitive to cyanide. Other mechanism for cyanide inhibition may be attributed to its affinity to Schiff base intermediates, e.g. ribulose diphosphate carboxylase and 2 – keto – 4 – hydroxyl glutarate aldolase involving formation of a cyanohydrin intermediate. Therefore, cyanide toxicity may not be attributed solely to a single biochemical lesion but a complex phenomenon3,4,7.
Perhaps of greatest importance is the formation of cyanomethemoglobin (CNMetHB), which is produced when the cyanide ion (CN-) react with MetHb. Methemoglobin is formed when hemoglobin (Hb) react with a variety of oxidants (eg, nitrite, dimethylaminopheno[DMAP], and ρ-aminopropiophenone [PAPP]. Cyanide may complex with endothelial-derived relaxing factor (EDRF, which is thought to be nitric oxide). Cyanide can interfere with the action of carbonic anhydrase and lower pH. Finally, albumin can exhibit enzymlike behavior and use bound elemental sulfur to detoxify cyanide. It is also theoretically possible to prevent entrance of cyanide ions into the cell by blocking transport mechanisms with substances such as DIDS3.
Intercellular enzymes may be involved for cyanide detoxification. The generalized reactions of rhodanase, mercaptopyruvate sulfurtransferase, thiosulfate reductase, and cysthathionase shown within the cell. The most important route of cyanide excretion is by formation of thiocyanate (SCN-), which is subsequently excreted in the urine. Thiocyanante possesses a less inherent toxicological hazard than cyanide, cyanate, or isocyanate. Thiocyanate formation is catalyzed directly by the enzyme rhodanase and indirectly via a spontaneous reaction between cyanide and the persulfide sulfur product of the enzyme 3-mercaptopyruvate sulfurtransferase and thiosulfate reductase. The mechanisms of all three enzymes as well as the pharmacokinetics of thiocyanate formation have been studied. Although 3-mercaptopyruvate functions to convert cyanide to this cyanate , it is instability and sulf-auto-oxidation at a basic pH may mask this effect. The enzymatic routes are efficient but have an insufficient capacity for detoxification in acute poisoning because of lack of sulfur donors. The mitochondrial sulfurtransferase reactions are exploited by the administration of sodium thiosulfate in the treatment of acute poisoning. It is still not known with any certainty, however, what specific endogenous sulfur sources participate in the formation of thiocyanate from cyanide3,4,7.
A minor route of metabolism is the oxidation of cyanide to cyanate (CNO-), which occur via enzymatic and nonenzymatic pathways. The interaction of cystine and cyanide to form 2-amino thiazoline 4-carboxylic acid and its tautomer accounts for approximately 20% of cyanide metabolism. However, the protection conferred by forming cyanate derivatives is limited because of the cell`s inability to utilize oxygen during cyanide intoxication. It is still controversial that hyperbaric oxygen or perhaps oxygen itself can reduce cyanide toxicity by competing with cyanide at some site (such as cytochrome oxidase in the mitochondria, which is thought to be a primary site for cyanide poisoning)
Combined, these metabolic routes detoxify 0.017mg of cyanide per kilogram of body weight per minute in the average human. Cyanide is one of the few chemical agents that does not follow Haber`s law, which states that the Ct (the product of concentration and time) necessary to cause to cause a given biological effect is constant over a range of concentration and times. For this reason, the LCt 50 (the vapor or aerosol exposure that is lethal to 50% of the exposed population) for a short exposure to a high concentration is different from a long exposure to a low concentration3.

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