Ethylene Glycol

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This substance is a liquid used in antifreeze, paints, polishes and cosmetics. As it has a sweet

Ethylene Glycol Metabolism
FIGURE 7.56 The metabolism of ethylene glycol. The NADH produced is utilized in the production of lactate. ADH: alcohol dehydrogenase; ALDH: aldehyde dehydrogenase; LDH: lactate dehydrogenase; GAO: glycolic acid oxidase; AO: aldehyde oxidase.

taste and is readily available it has been used as a poor man's alcohol, but it may also be ingested accidentally and for suicidal purposes. Diethylene glycol was once used as a vehicle for the drug sulphanilamide and when used for this it caused some 76 deaths.

The minimum lethal dose of ethylene glycol is about 100 ml and after ingestion death may occur within 24 h from damage to the CNS or more slowly (8-12 days) from renal failure. There seem to be three recognizable clinical stages:

a Within 30 min and lasting for perhaps 12 h, there is intoxication, nausea, vomiting, coma, convulsions, nystagmus, papilloedema, depressed reflexes, myoclonic jerks and tetanic contractions. Permanent optic atrophy may occur. b Between 12 and 24 h there is tachypnoea, tachycardia, hypertension, pulmonary oedema and congestive cardiac failure. c Between 24 and 72 h the kidneys become damaged giving rise to flank pain and acute renal tubular necrosis.

The clinical biochemical features reflect the biochemical and physiological effects. Thus, there is reduced plasma bicarbonate, low plasma calcium and raised potassium. Crystals, blood and protein may all be detected in the urine (crystalluria, haematuria and proteinuria, respectively), and the urine may have a low specific gravity.

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 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,

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glucose metabolism, Krebs' cycle, protein synthesis, RNA synthesis and DNA replication for example. The consequences of this are as follows:

i acidosis due to lactate, oxalate and the other acidic metabolites; this results in metabolic distress and physiological changes ii loss of calcium as calcium oxalate iii deposition of crystals of calcium oxalate in the renal tubules and brain iv inhibition of various metabolic pathways leading to accumulation of organic acids v impairment of cerebral function by oxalate and damage by crystals; also some of the aldehyde metabolites may impair cerebral function vi damage to renal tubules by oxalate crystals leading to necrosis.

Thus the pathological damage includes cerebral oedema, haemorrhage and deposition of calcium oxalate crystals. The lungs show oedema, and occasionally calcium oxalate crystals and degenerative myocardial changes may also occur. There is degeneration of proximal tubular epithelium with calcium oxalate crystals and fat droplets detectable in tubular epithelial cells. The degeneration of distal tubules may also be seen.

Ethylene glycol is more toxic to humans than animals, and in general the susceptible species are those which metabolize the compound to oxalic acid, although this is quantitatively a minor route. The treatment of poisoning with ethylene glycol reflects the mechanism and biochemical effects. Thus, after standard procedures such as gastric lavage to reduce absorption and supportive therapy for shock and respiratory distress, patients are treated with the following:

a 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

b intravenous sodium bicarbonate; this corrects the acidosis—animal studies have shown that this increases the LD50 by around four times c calcium gluconate; this corrects the hypocalcaemia d dialysis to remove ethylene glycol.

Thus the treatment of poisoning with ethylene glycol is a logical result of understanding the biochemistry of the toxicity.

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Responses

  • Paride
    What are the toxic intermediates of ethylene glycol metabolsim?
    2 months ago

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