Metabolism of ethylene glycol

Metabolism of ethylene glycol and methanol to their toxic products can be blocked by inhibiting the enzyme alcohol dehydrogenase with a competing drug, such as fomepizole (4-methylpyrazole). Ethanol is also an effective antidote, but it can be difficult to achieve a safe and effective blood level. 

However, there are known instances of differences in the preferred route of metabolism, which are important in toxicity, as well as simple differences in the route of a particular oxidation. For example, the oxidative metabolism of ethylene glycol gives rise to either carbon dioxide or oxalic acid (Fig. 5.7). The relative importance of these two pathways is reflected in the toxicity. Thus, the production of oxalic acid is in the order cat>rat> rabbit, and this is also the order of increasing toxicity (Fig. 5.8). The aromatic hydroxylation of aniline (Fig. 5.9) shows marked species differences in the position of substitution, as shown in Table 5.9. Thus carnivores such as the ferret, cat, and dog excrete mainly o-aminophenol, whereas herbivores such as the rabbit and guinea pig excrete mainly p-aminophenol. The rat, an omnivore, is intermediate. 

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

Figure 5.8 Species differences in the metabolism of ethylene glycol to oxalate after increasing doses. Species used were cats (o), rats ( ), and rabbits ( ). Source. From Refs. 20 and 21.

Figure 7.84 The metabolism of ethylene glycol. The NADH produced is used in the production of lactate, the level of which will rise dramatically in poisoning cases. Abbreviations. ADH, alcohol dehydrogenase ALDH, aldehyde dehydrogenase LDH, lactate dehydrogenase GAO, glycolic acid oxidase AO, aldehyde oxidase.

Ethylene glycol, HOCH2CH2OH, is an extremely toxic did because its oxidation products are also toxic. Draw the oxidation products formed during the metabolism of ethylene glycol. 

Ethylene glycol, present in antifreeze products, may be ingested accidentally or for the purpose of inebriation or suicide. Ethylene glycol itself is relatively nontoxic, and its initial CNS effects resemble those of ethanol. However, metabolism of ethylene glycol by ADH results in the formation of a number of acid metabolites, including oxalic acid and glycolic acid (Figure 34-16). 

Ghanayem BI, Blair PC, Thompson MB, et al. 1987a. Effect of age on the toxicity and metabolism of ethylene glycol monobutyl ether (2-butoxyethanol) in rats. Toxicol Appl Pharmacol 91(2) 222-234. 

However, there are known instances of differences in the preferred route of metabolism which are important in toxicity, as well as simple differences in the route of a particular oxidation. For example, the oxidative metabolism of ethylene glycol gives rise to either carbon dioxide or oxalic acid (figure 5,5). The relative importance of these two pathways... 

Administer fomepizole (see p 448) or ethanoi (p 444) to saturate the enzyme alcohol dehydrogenase and prevent metabolism of ethylene glycol to its toxic metabolites. Indications for therapy include the following ... 

Administer pyridoxins (see p 499), folate (p 447), and thiamine (p 505), cofactors required tor the metabolism of ethylene glycol that may alleviate toxicity by enhancing metabolism of glyoxylic acid to nontoxic metabolites. 

The answer Is 2 /// Hh Ahhcxjgh 4-methylpyrazole ( MP) prevents the formation of acid intermediates in dogs that have ingested ethylene glycol. It has not been shown effective in cats and is not currently recommended as an antidote for this species. Ethanol has been used for many years to reduce the metabolism of ethylene glycol... 

Loss of antidote effectiveness because of metabolism of ethylene glycol to toxic intermediates... 

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