Ethylene glycol metabolism

Wiegant WM, JAM de Bont (1980) A new route for ethylene glycol metabolism in Mycobacterium E44. J Gen Microbiol 120 325-331. 

Ethanol this competes with ethylene glycol for alcohol dehydrogenase, but as it is a better substrate, the first step in ethylene glycol metabolism is blocked—animal studies have shown that this doubles the LD50. 

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]. 

Hypoventilation causes retention of C02 by the lungs, which can lead to a respiratory acidosis. Hyperventilation can cause a respiratory alkalosis. Metabolic acidosis can result from accumulation of metabolic acids (lactic acid or the ketone bodies p-hydroxybutyric acid and acetoacetic acid), or ingestion of acids or compounds that are metabolized to acids (methanol, ethylene glycol). Metabolic alkalosis is due to increased HC03, which is accompanied by an increased pH. Acid-base disturbances lead to compensatory responses that attempt to restore normal pH. For example, a metabolic acidosis causes hyperventilation and the release of C02, which tends to lower the pH. During metabolic acidosis, the kidneys excrete NH4+, which contains H+ buffered by ammonia. 

B. Pharmacokinetics. Ethylene glycol is well absorbed. The volume of distribution (Vd) is about 0.8 L/kg. It is not protein bound. Metabolism is by alcohol dehydrogenase with a half-life of about 3-5 hours. In the presence of ethanol or fomepizole (see below), which block ethylene glycol metabolism, elimination is entirely renal with a half-life of about 17 hours. 

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-... 

A simple cyclic diester of carbonic acid is ethylene carbonate (7.96), a chemical with a toxicity profile resembling that of ethylene glycol (7.97). Metabolic studies have confirmed that ethylene carbonate is hydrolyzed very rapidly to ethylene glycol (whose oxidation is discussed in Chapt. 2 in [7]) and C02. Indeed, rats given an oral dose of ethylene carbonate did not excrete the unchanged xenobiotic in detectable amounts, and blood levels of the diester were ca. 100-fold smaller than those of ethylene glycol [178],... 

On the other hand, Haines and Alexander reported that PEG 20,000 might be hydrolyzed by an extracellular enzyme of Pseudomonas aeruginosa ( ). According to our experiments, PEG 6000 was not hydrolyzed by an extracellular enzyme (the supernatant fluid of a culture), but it was metabolized by washed cells and the culture could not utilize ethylene glycol or diethylene glycol which might be the hydrolysis products of PEG. 

More recently, Pearce and Heydeman suggested non-oxidative removal of ethylene glycol units as acetaldehyde by a membrane-bound, oxygen-sensitive enzyme of a novel type, i.e., diethylene glycol lyase (18). Schoberl suggested that PEG was catabolized by Ci step, liberating formate which was metabolized by a serine pathway (19). 

Toxicology. Dipropylene glycol methyl ether (DPGME) at very high concentrations causes narcosis in animals, and it is expected that severe exposure will produce the same effect in humans. Because the propylene glycol ethers are metabolized differently from the ethylene glycol ethers, they are not associated with potent teratogenic, spermatotoxic, or hematopoietic effects. ... 

Toxieology. Ethylene glycol aerosol causes irritation of the upper respiratory tract ingestion can cause central nervous system depression, severe metabolic acidosis, liver and kidney damage, and pulmonary edema. 

Methanol and ethylene glycol are contaminants of illicit ethanol, and can be taken as ethanol substitutes. Both agents cause severe metabolic acidosis with a high anion gap. 

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... 

For patients who have ingested more than 30 ml of (pure) methanol or ethylene glycol, dialysis is recommended, and haemodialysis is more effective than peritoneal dialysis. Dialysis both removes the alcohols and their metabolites, and corrects the renal and metabolic disturbances and so is the preferred treatment in severe poisoning. The maintenance dose of ethanol required may be tripled during haemodialysis as ethanol is also removed. Early treatment is indicated if ethylene glycol concentrations are above 20 mg/100 ml (200 mg/1), if the arterial pH is below 7.3, if serum bicarbonate concentrations are less than 20 mM/1, and when there are oxalate crystals in the urine. 

All patients with methanol toxicity should be given folic acid 50 milligrams intravenously every 4 hours to increase the metabolism of formic acid. In ethylene glycol ingestion, folate, thiamine and pyri-doxine should all be administered, to enhance the metabolism of the poison to non-toxic products, and minimize oxalic acid production. Calcium supplements are required for symptomatic hypocalcaemia. 

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... 

The a-oxidation pathway ofTV-nitrosodiethanolamine metabolism (Figure 2) leads to the formation of an a-hydroxynitrosamine that rapidly decomposes, producing glycol aldehyde, acetaldehyde, ethylene glycol and molecular nitrogen. The latter is assumed to arise from a reactive (2-hydroxyethyl)diazonium ion, which probably is responsible for the formation of 2-hydroxyethylated adducts in DNA (Scherer et al., 1991 Loeppky etal., 1998 Loeppky, 1999). 

Three stages of ethylene glycol overdose occur. Within the first few hours after ingestion, there is transient excitation followed by CNS depression. After a delay of 4-12 hours, severe metabolic acidosis develops from accumulation of acid metabolites and lactate. Finally, delayed renal insufficiency follows deposition of oxalate in renal tubules. The key to the diagnosis of ethylene glycol poisoning is recognition of anion gap acidosis, osmolar gap, and oxalate crystals in the urine in a patient without visual symptoms. 

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... 

Ethanol Higher affinity for alcohol dehydrogenase used to reduce metabolism of methanol and ethylene glycol to toxic products ... 

Normally, the sum of the cations exceeds the sum of the anions by no more than 12-16 mEq/L (or 8-12 mEq/L if the formula used for estimating the anion gap omits the potassium level). A larger-than expected anion gap is caused by the presence of unmeasured anions (lactate, etc) accompanying metabolic acidosis. This may occur with numerous conditions, such as diabetic ketoacidosis, renal failure, or shock-induced lactic acidosis. Drugs that may induce an elevated anion gap metabolic acidosis (Table 58-1) include aspirin, metformin, methanol, ethylene glycol, isoniazid, and iron. 

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