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Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Two enzyme systems are involved in the metabolism of alcohol; one is cytosolic, and the other is microsomal. Alcohol and aldehyde dehydrogenases are cytosolic components mainly responsible for the first two steps of alcohol oxidation.57,233,288,544 The second alcohol oxidizing enzyme complex is bound to the microsomal fraction.36,549 Alcohol dehydrogenase is found mainly in the liver. This enzyme is the rate-limiting step in the metabolism of alcohol (Figure 34). In the human liver, there are three to seven active alcohol dehydrogenase isoenzyme fractions with variable activity.280,565,610 The isoenzymes composition varies widely from and with different turnover rates, thus explaining the individual and ethnic variations. Aldehyde dehydrogenase is present in many tissues,564 and several isoenzymes have been identified.234,246,425,474 Animal experiments have shown that with alcohol pretreatment the activity of alcohol dehydrogenase increases. This adaptive change may be important in the development of tolerance in alcoholism.
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
The classic examples of alcohol dehydrogenase-mediated bioactivation are in the toxicity of methanol and ethylene glycol. Formate, a metabolite of methanol, causes toxicity to the retina leading to blindness; and oxalate, a metabolite of ethylene glycol, forms a precipitant in kidney tubules leading to stone formation. Leading to hepatotoxicity, alcohol dehydrogenase converts allyl formate and allyl alcohol to the reactive aldehyde, acrolein (Rees and Tarlow, 1967; Reid, 1972). Since alcohol dehydrogenase has a periportal distribution in the liver, allyl formate and allyl alcohol induce periportal necrosis.
Alcohol
Published in Jason Payne-James, Richard Jones, Simpson's Forensic Medicine, 2019
Jason Payne-James, Richard Jones
Ethanol is converted into acetaldehyde via the actions of alcohol dehydrogenase resulting in the production of acetic acid and then acetaldehyde. Acetaldehyde is responsible for most of the clinically observed side-effects produced by alcohol. The measured alcohol concentration depends on both weight and sex because these two factors determine the total volume of body water and consequently the BAC. In general terms, the more a person weighs, the larger the volume of water their body will contain. After consuming equal amounts of alcohol, someone who is obese or has a greater proportion of body fat will have a lower BAC than a thin person. Females have more fat tissue than males of the same weight and, therefore, a smaller volume of body water. As a result, the BAC will be slightly higher in women than in men after consuming an equal amount of alcohol.
Characteristics of analytically confirmed gamma-hydroxybutyrate (GHB) positive patients in the emergency department: presentation, poly-drug use, disposition and impact on intensive care resource utilisation
Published in Clinical Toxicology, 2023
Peter Stockham, Emma Partridge, Sam Alfred, Laura Boyle, Andrew Camilleri, Hannah Green, Daniel Haustead, Melissa Humphries, Chris Kostakis, Jake Mallon
Gamma-hydroxybutyrate may be dosed directly, or as either of its metabolic precursors gamma-butyrolactone or 1,4-butanediol. Gamma-butyrolactone is pharmacologically inactive but is converted to GHB by serum lactonase, while 1,4-butanediol is an aliphatic alcohol converted to GHB in a 2-step process involving alcohol dehydrogenase and aldehyde dehydrogenase. Alcohol dehydrogenase metabolism is inhibited by co-ingestion with ethanol, which can alter the onset and duration of GHB effects following 1,4-butanediol use. Animal studies suggest gamma-butyrolactone is more rapidly absorbed than GHB and may result in higher serum concentrations [3]. Gamma-hydroxybutyrate is rapidly absorbed with the onset of effects within 15–30 min of administration, with time to peak plasma concentrations of 20–57 min [4–6]. It is rapidly eliminated with first-order kinetics at a low dose resulting in a mean elimination half-life of 30–52 min [2,4–6]. Enzyme saturation occurs at higher doses, resulting in zero-order kinetics that may prolong the elimination and duration of effects [7,8]. Gamma-hydroxybutyrate exhibits a steep dose-effect curve, and small increases in dose may cause disproportionate increases in toxicity [2]. Complications of overdose include a reduced level of consciousness, coma, hypoventilation, apnoea, bradycardia, hypotension, and myoclonus. Treatment is essentially supportive, focusing on airway protection and respiratory support [2,9].
Variable sensitivity to diethylene glycol poisoning is related to differences in the uptake transporter for the toxic metabolite diglycolic acid
Published in Clinical Toxicology, 2023
Julie D. Tobin, Courtney N. Jamison, Corie N. Robinson, Kenneth E. McMartin
Diethylene glycol (DEG) is a colorless organic solvent that is found in industrial lubricants and chafing fuel. It has also been mistakenly used in pharmaceutical formulations as a cheaper alternative to glycerin or has been an adulterant in the procured glycerin [1]. Ingestion of these adulterated pharmaceutical preparations has resulted in several epidemic poisonings, with multiple fatalities. The hallmark sign of DEG poisoning is renal failure or acute kidney injury (AKI), while other clinical manifestations include metabolic acidosis, mild to moderate hepatotoxicity, and a delayed peripheral neuropathy [2–4]. The kidney injury observed in many patients is characterized by remarkable necrosis of the proximal tubular epithelium [5]. Diethylene glycol undergoes metabolism first by alcohol dehydrogenase, eventually yielding two primary metabolites, diglycolic acid (DGA) and 2-hydroxyethoxyacetic acid (2-HEAA). A study by Besenhofer et al. [6] showed that DEG toxicity is blocked when metabolism by alcohol dehydrogenase is inhibited in rats, suggesting that it is a metabolite of DEG that is responsible for the toxicity and not the parent compound. Moreover, several studies have shown that direct DGA administration both in vitro and in vivo mimic the toxicity found in DEG studies, suggesting that DGA is the metabolite responsible for the toxicity [7–9]. Furthermore, DGA accumulation of up to 100-fold is found in kidney tissue after DEG administration, compared to concentrations in the blood [10].
Fomepizole dosing during continuous renal replacement therapy – an observational study
Published in Clinical Toxicology, 2022
Yvonne E. Lao, Trond Vartdal, Sten Froeyshov, Brian Latimer, Christiane Kvaerner, Marija Mataric, Peter Holm, Siri Foreid, Dag Jacobsen, Kenneth McMartin, Knut Erik Hovda
Methanol and ethylene glycol are toxic alcohols with a potential fatal outcome when poisoned. Large outbreaks of methanol poisoning with high mortality are regularly reported [1,2], as are case reports of intentional or accidental ingestion of ethylene glycol [3,4]. Early treatment with the antidotes ethanol or fomepizole is effective and lifesaving [5]. Both substances act by inhibiting the alcohol dehydrogenase enzyme, and thus preventing the formation of the toxic metabolites (formic acid from methanol and glycolic acid from ethylene glycol). Although ethanol can cause a pronounced central nervous system (CNS) depression, it also requires frequent monitoring of plasma ethanol. Fomepizole, on the other hand, has limited side effects (e.g., headache and dizziness), and does not require monitoring of plasma concentration. Treatment guidelines therefore recommend fomepizole as the antidote of choice [5]. Plasma concentrations of fomepizole above 10 µmol/L are considered effective and will prevent formation of the toxic metabolites, based on studies done in non-human primates [6,7].