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Biocatalytic Reduction of Organic Compounds by Marine-Derived Fungi
Published in Se-Kwon Kim, Marine Biochemistry, 2023
Gabriel S. Baia, David E. Q. Jimenez, André Luiz Meleiro Porto
Medium-chain dehydrogenase/reductase (MDR) oxidoreductases form a large enzyme superfamily of 1000 members [9]. These enzymes represent many different activities, for example, alcohol dehydrogenases (ADHs) [9]. The ADHs are enzymes that can transform ketones/aldehydes to alcohols and vice versa at the expense of a nicotinamide cofactor that acts as hydride donor and acceptor [9]. Gonzalo et al. [10] used ADHs enzymes to the reduction of ketones to alcohol derivatives as shown in Figure 15.3. The reduction reaction conditions were 30°C and 300 rpm in micro-aqueous hexane media for 40–42 h. The ADHs resulted in 67–96% conversion and >99% ee for all products [10].
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
Alcohol dehydrogenase (EC 1.1.1.1.) is ubiquitous in nature. The enzyme is predominately cytosolic. Its highest activity is in liver, but there is appreciable activity in stomach, lung, intestine, and kidney. Alternate biotransformation pathways for alcohols include glucuronide conjugation and catalase-dependent and P450-linked enzyme (ethanol-inducible subfamily) oxidation. Alcohol structure determines the extent of biotransformation by a particular pathway. Primary and secondary aliphatic and aromatic alcohols are good substrates, but hindered, and tertiary alcohols are poor substrates. Selected aldehydes and ketones can also be reduced by alcohol dehydrogenase.
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].
Single versus continued dosing of fomepizole during hemodialysis in ethylene glycol toxicity
Published in Clinical Toxicology, 2021
Alexander M. Sidlak, Ryan T. Marino, James P. Van Meerbeke, Anthony F. Pizon
The potential harm from failing to maintain alcohol dehydrogenase inhibition during HD would be the accumulation of EG metabolites which could then produce end organ damage. We therefore sought to analyze measures that would serve as proxies for a failure of hemodialysis to adequately clear EG metabolites without ADH inhibition. We found a non-significant trend toward an increased LOS, a higher creatinine upon discharge, and more adverse effects in the MD group. No increase in adverse effects were found in the SD group. These findings were likely driven by the fact that the MD group was potentially more delayed in presentation. There was a trend toward more renal dysfunction on presentation and longer durations of HD in the MD group, which may have affected the number of doses of fomepizole given and made it difficult to directly compare outcomes between the groups.