Toxic metabolites ethylene glycol

The mechanism of toxicity of ethylene glycol involves metabolism, but unlike previous examples, this does not involve metabolic activation to a reactive metabolite. Thus, ethylene glycol is metabolized by several oxidation steps eventually to yield oxalic acid (Fig. 7.84). The first step is catalyzed by the enzyme alcohol dehydrogenase, and herein lies the key to treatment of poisoning. The result of each of the metabolic steps is the production of NADH. The imbalance in the level of this in the body is adjusted by oxidation to NAD coupled to the production of lactate. There is thus an increase in the level of lactate, and lactic acidosis may result. Also, the intermediate metabolites of ethylene glycol have metabolic effects such as the inhibition of oxidative phosphorylation, glucose metabolism, Krebs cycle, protein synthesis, RNA synthesis, and DNA replication. 

These acid metabolites are responsible for much of the toxicity of ethylene glycol, the clinical manifestations of which include neurological abnormalities (CNS depression in severe cases, coma and convulsions), severe metabolic acidosis, acute renal failure, and cardiopulmonary failure. The serum concentration of glycolic acid correlates more closely with clinical symptoms and mortality than does the concentration of ethylene glycol. Secause of the rapid elimination of ethylene glycol (ti/2 3 hours), its serum concentration may be low or undetectable at a time when that for glycolic acid remains elevated. Thus the determi-... 

The mechanism of toxicity of ethylene glycol involves metabolism, but unlike previous examples this does not involve metabolic activation to a reactive metabolite. Thus, ethylene glycol is metabolized by several oxidation steps eventually to yield oxalic acid (figure 7,56). The first step is catalysed by the... 

ADH also has clinical significance in the metabolism of methanol and ethylene glycol, two drugs with toxic metabolites. Methanol is oxidized by ADH to formaldehyde, which damages the retina and can cause blindness. Ethylene glycol is metabohzed by ADH to oxalic acid, which has renal tox-... 

Ethylene glycol (and toxic metabolites) Central nervous system... 

Ethylene glycol is rapidly metabolised to glyco-laldehyde, then glycolic acid, glyoxylic acid and finally to oxalic acid. The metabolites are toxic to kidneys, brain and heart. 

Management of methanol and ethylene glycol poisoning is similar. Symptomatic support of respiration and circulation is augmented by correction of metabolic acidosis with intravenous bicarbonate infusion, and control of seizures with diazepam. Ethanol inhibits the metabolism of methanol and ethylene glycol to the toxic metabolites, and can give time for further treatment. The goal is to maintain blood ethanol concentrations between 100 and 150 mg per decilitre, sufficient to saturate alcohol... 

Ethylene glycol Ethanol Blocks metabolism to toxic metabolite... 

Mechanism of Action An alcohol dehydrogenase inhibitor that inhibits the enzyme that catalyzes the metabolism of ethanol, ethylene glycol, and methanol to their toxic metabolites. Therapeutic Effect Inhibits conversion of ethylene glycol and methanol into toxic metabolites. 

Inpatients with high ethyleneglycol levels (>50 mg/dl), significant metabolic acidosis or renal failure, consider hemodialysis to remove ethylene glycol and its toxic metabolites... 

As with methanol poisoning, early fomepizole or ethanol infusion and hemodialysis are standard treatments for ethylene glycol poisoning. Fomepizole, an inhibitor of alcohol dehydrogenase, has FDA approval for treatment of ethylene glycol poisoning in adults based on its ability to decrease concentrations of toxic metabolites in blood and urine and to prevent... 

Ethanol Multiple effects on neurotransmitter receptors, ion channels, and signaling pathways Antidote in methanol and ethylene glycol poisoning Zero-order metabolism duration depends on dose Toxicity Acutely, CNS depression and respiratory failure chronically, damage to many systems, including liver, pancreas, GI tract, and central and peripheral nervous systems Interactions Induces CYP2E1 Increased conversion of acetaminophen to toxic metabolite... 

Fomepizole Inhibits alcohol dehydrogenase, prevents conversion of methanol and ethylene glycol to toxic metabolites Methanol and ethylene glycol poisoning Orphan drug. Toxicity Headache, nausea, dizziness, rare allergic reactions... 

COOH Figure 5.7 Metabolism of ethylene glycol showing the production of, . the toxic metabolite. 

Hemodialysis is more efficient than peritoneal dialysis and has been well studied. It assists in correction of fluid and electrolyte imbalance and may also enhance removal of toxic metabolites (eg, formate in methanol poisoning, oxalate and glycolate in ethylene glycol poisoning). The efficiency of both peritoneal dialysis and hemodialysis is a function of the molecular weight, water solubility, protein binding, endogenous clearance, and distribution in the body of the specific toxin. 

Toxicity. Ethylene glycol itself is probably non-toxic and the serious toxic effects are due to the metabolites. In adults the... 

Ethylene glycol is sometimes used in suicide attempts. It is not itself toxic, but is converted to toxic metabolites. Conversion to glycoaldehyde by alcohol dehydrogenase is the rate-limiting step, and further metabohsm jdelds gly-colate, glyoxylate, and oxalate. 

Treatment should include correction of metabolic acidosis, inhibition of ethylene glycol metabolism and if necessary, extracorporeal elimination of the parent alcohol and metabolites. Acidemia likely increases tissue penetration of toxic metabolites and hinders renal clearance. Although evidence is lacking, bicarbonate administration should be given to correct acidemia. Although more expensive, fomepizole is preferred to ethanol for ADH inhibition due to proven efficacy, predictable pharmacokinetics, and lack of adverse effects [105]. Inhibition of ADH with fomepizole prevents formation of toxic metabolites and renal injury, and improves add-base status [106]. Elimination half-life of ethylene glycol with fomepizole in patients with preserved renal function is approximately 20 hours [107]. Pyridoxine and thiamine should be administered to promote glyoxyhc add conversion less toxic metabolites than oxalate [108]. 

McMartin KE, Wallace KB. Calcium oxalate monohydrate, a metabolite of ethylene glycol, is toxic for rat renal mitochondrial function.Toxicol Sci 2005 84 195-200. 

Ethylene glycol and glycoaldehyde have an intoxicating effect on the central nervous system that can lead to ataxia, sedation, coma, and respiratory arrest. The metabolic acidosis reported in toxicity is due to the acidic metabolites, especially glycolic acid. Ethylene glycol itself may result in a large osmolar gap. Oxalic acid may combine with calcium to form calcium oxylate crystals. The precipitation of these crystals in tissue may result in renal failure and hypocalcemia. 

Spermatocytes Ethylene glycol monomethyl ether (EGME) was formerly used in the semiconductor industry and has been shown to elicit a relatively specific toxicity primarily to pachytene spermatocytes. It is not EGME, but its metabolite methoxyacetic acid, that is thought to be responsible for damaging spermatocytes. It has been found that the methoxyacetic acid disrupts protein kinase activities in dividing mitotic cells, and that cotreatment of seminiferous tubules with EGME and protein kinase inhibitors blocked the cytotoxic effects to spermatocytes. 

Fraser AP, MacNeil W. Colorimetric and gas chromatographic procedures for glycolic acid in serum the major toxic metabolite of ethylene glycol. Clin Toxicol 1993 31 397-405. 

Ingested ethylene glycol is metabolized to glycolic and oxalic acids and other acidic metabolites. Its metabolism leads to an acidosis with high anion and osmolal gaps. Accumulation of toxic metabohtes may contribute to lactic acid production that further contributes to the acidosis. Precipitation of calcium oxalate and hippurate crystals in the urinary tract... 

CO2 production most closely followed ethylene glycol production. The study authors suggested that these results indicate that, in rats, overall metabolism of 2-butoxyethanol to 2-butoxyacetic acid, the hemolytic metabolite, was linearly related to the exposure concentration up to a concentration that caused severe toxicity (438 ppm). Assuming that the toxicity of inhaled 2-butoxyethanol is directly proportional to the formation of 2-butoxyacetic acid, the authors suggested that the toxicity of inhaled 2-butoxyethanol can be expected to be linearly related to the exposure concentration up to exposure concentrations that cause mortality. 

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