Glycolic acid metabolism

D,L-Lactic acid and glycolic acid (metabolism, excretion) harmlessly eliminate the final degradation product (Middleton and Tipton, 2000)... 

More than a dozen biocompatible and biodegradable polymers have been described and studied for their potential use as carriers for therapeutic proteins (Table 13.5). However, some of the monomer building blocks such as acrylamide and its derivatives are neurotoxic. Incomplete polymerization or breakdown of the polymer may result in toxic monomer. Among the biopolymers, poly-lactide cofabricated with glycolide (PLG) is one of the most well studied and has been demonstrated to be both biocompatible and biodegradable [12]. PLG polymers are hydrolyzed in vivo and revert to the monomeric forms of glycolic and lactic acids, which are intermediates in the citric acid metabolic pathway. 

It seems incredible now that no one bothered to check the toxicity of the solvent Watkins used. Had they bothered to peruse the scientific literature, they would have discovered that diethylene glycol is metabolized in the body to oxalic acid, a potent kidney toxin that can kill. Simple animal experiments would have confirmed the risk. 

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. 

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.

Degradation leads to the formation of lactic acid and glycolic acid, which are normal intermediates in carbohydrate metabolism. 

Many poisonings by methanol and ethylene glycol occur each year. Alcoholics occasionally drink ethanol that has been denatured by the addition of methanol. Methanol is oxidized to formic acid, which may cause blindness and death. Dogs are often poisoned by sweet-tasting ethylene glycol when antifreeze is left in an open container. Once the glycol is metabolized to oxalic acid, the dog s kidneys fail, causing death. 

There are three known metabolic pathways to 3-deoxyulosonic acids. In the first, aldonic acids, formed by oxidation of aldopyranoses to the corresponding lactones, are dehydrated to the ulosonic acids (see Fig. 6). Thus, D-arabinose is converted by way of D-arabinonic acid to 3-deoxy-o-ffZj/cero-pentulosonic acid. The latter is then subjected to oxidative cleavage, yielding pyruvic and glycolic acids. L-Arabinose is oxidized and dehydrated to the 3-deoxy-L-g Z2/cero-pentulosonic acid, which is further oxidized to... 

Early laboratory findings include a high serum osmolal gap from the ethylene glycol. An extreme metabolic acidosis with greatly elevated anion gap follows, principally from glycolic acid [100]. Hypocalcemia and hyperkalemia may be evident and urinalysis may reveal calcium oxalate crystalluria, hematuria, and proteinuria. 

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. 

Some of these differences can be attributed to variations in detoxication mechanisms. For example, the loss of consciousness induced in several species of laboratory animals by hexobarbital (a barbiturate derivative that depresses the central nervous system (CNS)) shows marked differences these are attributable to the activity of the detoxication enzyme that inactivates this chemical. In the mouse, the activity of the detoxifying enzyme is 16-fold greater than that in the dog, which is reflected by 12 min of hexobarbital-induced sleep in the mouse versus 315 min of sleep in the dog. There are other examples of species-related differences in the ability to detoxify chemicals that consequently result in differences in toxicity. Other examples include the industrial chemicals, ethylene glycol and aniline. Ethylene glycol is metabolized to oxalic acid, which is responsible for its toxicity, or to carbon dioxide. The rank order of ethylene glycol toxicity in animals is as follows cat rat rabbit this is the same for the extent of oxalic acid production. Aniline is metabolized in the cat and dog mainly to o-aminophenol, and these species are more prone to toxicity however, in the rat and hamster aniline is metabolized mainly to I-aminophenol and thus these species are less susceptible to aniline toxicity. 

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). 

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-... 

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... 

Resorcinol solutions have been used in combination with glycolic acid, trichloroacetic acid (TCA) and 5-fluorouracil (5-FU). Many modified versions of Jessner s solution have been presented, containing kojic acid, hydroquinone, etc. The effectiveness of these resorcinol solutions depends on skin preparation, skin sensitivity and thickness, the type of applicator and the force of application, the number of coats applied, the type of solution used, the quality of the solution s preparation, etc. Moreover, products with a tyrosinase-inhibiting action (kojic acid, hydroquinone, etc.) only produce their effect in the long term. Single application of these products cannot treat melasma in any way. Only repeated applications, allowing the gradual absorption of products that inhibit melanocyte metabolism, can be considered as an effective treatment. 

Kidney damage results from precipitation of oxalate crystals in the convoluted tubules. The elevated anion-gap metabolic acidosis is caused by glycolic acid and lactic acid. The latter is formed from pyruvate due to a shift in the redox potential favoring the production of lactate. The treatment is the same as that for methanol intoxication. 

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