Liver Diseases
George Feuer, Felix A. de la Iglesia in Molecular Biochemistry of Human Disease, 2020
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.
Interaction of Alcohol with Medications and Other Drugs
John Brick in Handbook of the Medical Consequences of Alcohol and Drug Abuse, 2012
Disulfiram (Antabuse) is a medication that has been used in the treatment of alcoholism since the 1950s. Alcohol is metabolized by alcohol dehydrogenase to acetaldehyde, which is metabolized by aldehyde dehydrogenase. Disulfiram inhibits the enzyme aldehyde dehydrogenase resulting in the accumulation of acetaldehyde in the body. Acetaldehyde is highly toxic and has many sympathomimetic effects. The buildup of acetaldehyde can cause an unpleasant, aversive reaction characterized most commonly by the symptoms of facial flushing, nausea, vomiting, breathing difficulties, and headache. The severity of the reaction usually depends on the amount of alcohol consumed but some people are extremely sensitive to acetaldehyde toxicity. In extreme cases, respiratory depression, cardiovascular collapse, cardiac arrhythmias, unconsciousness and convulsions leading to death can occur.
Alcohol
Jason Payne-James, Richard Jones in Simpson's Forensic Medicine, 2019
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.
On the path toward personalized medicine: implications of pharmacogenetic studies of alcohol use disorder medications
Published in Expert Review of Precision Medicine and Drug Development, 2020
Steven J. Nieto, Erica N. Grodin, Lara A. Ray
Several candidates and genome-wide association studies implicate alcohol metabolism genes in risk for AUD. Unfortunately, few studies have examined the influence of these genes on AUD medications. For the most part, alcohol metabolism occurs in the liver wherein several enzymes oxidize alcohol. Alcohol dehydrogenase converts alcohol to acetaldehyde, a potentially toxic metabolite, which is usually rapidly converted to acetic acid by the enzyme acetaldehyde dehydrogenase. Acetaldehyde dehydrogenase (ALDH) occurs in several genetic forms with differential activity. More than one third of individuals with East Asian ancestry inherit the inactive form of ALDH2 [79]. For these individuals, alcohol consumption increases levels of acetaldehyde, causing several negative physiological consequences, such as nausea and vomiting. Thus, inactive ALDH2 may enhance treatment response to drugs that block acetaldehyde metabolism, such as disulfiram. Yoshimura et al. [80] found that alcohol dependent individuals (ICD-9 criteria) with the inactive ALDH2 genotype had higher rates of abstinence from alcohol when treated with disulfiram relative to carriers treated with placebo. Prospective clinical studies with larger sample sizes are needed to examine the influence of alcohol metabolism genes.
Taxifolin, a novel food, attenuates acute alcohol-induced liver injury in mice through regulating the NF-κB-mediated inflammation and PI3K/Akt signalling pathways
Published in Pharmaceutical Biology, 2021
Chuanbo Ding, Yingchun Zhao, Xueyan Chen, Yinan Zheng, Wencong Liu, Xinglong Liu
The liver is an important part of the body’s metabolic system, which can remove many harmful substances from the body, but it is also attacked and damaged by many harmful substances. When the body is stimulated by a large amount of alcohol, about 90% of the alcohol content is metabolized in the liver, which will cause severe hepatotoxicity. Alcohol dehydrogenase in the cytoplasm of liver cells will metabolize ethanol into acetaldehyde, aldehyde dehydrogenase (ALDH) or other isoenzymes. The lack of acetaldehyde dehydrogenase leads to the accumulation of acetaldehyde, and excess acetaldehyde produces a large amount of reactive oxygen species (ROS), which in turn leads to oxidative stress, hepatic stellate cells (HSCs) and cause severe hepatotoxicity (Cui et al. 2019). In addition, the hepatocytes were directly stimulated by the ethanol and acetaldehyde accumulated in the liver, which can cause degeneration and necrosis of liver cells, and aggravate hepatocyte apoptosis (Li et al. 2017). Furthermore, studies have shown that oxidative stress injury caused by excessive accumulation of acetaldehyde may promote the excessive release of macrophages and many proinflammatory factors, including TNF-α, IL-1β, nuclear factor-kappa B (NF-κB), nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) (Li et al. 2016). Therefore, inflammatory injury is a key pathological process leading to the development of alcoholic liver toxicity, which also provides many target references for the clinical treatment of alcoholic liver toxicity.
Ethanol and its metabolites: update on toxicity, benefits, and focus on immunomodulatory effects
Published in Drug Metabolism Reviews, 2019
Brendan Le Daré, Vincent Lagente, Thomas Gicquel
Cytosolic alcohol dehydrogenase (ADH) is the major enzyme responsible for the phase I oxidative metabolism of ethanol, producing acetaldehyde and reduced nicotinamide adenine dinucleotide (NADH) (Cederbaum 2012). The enzyme is predominantly expressed by hepatocytes but is also found in the gastrointestinal tract, lung and kidneys (Crabb 1995; Edenberg 2000). In humans, seven genes (ADH1 to ADH7) code, respectively, for ADH’s different subunits (α, β1, β2, β3, γ1, γ2, π, χ, σ, and μ) (Cederbaum 2012). These subunits bind together in pairs to form isoenzymes classified into five classes (ADH class I to ADH class V), depending on their enzymatic proprieties (Crabb 1995). Class I ADH (formed from subunits encoded by ADH1, ADH2, and ADH3) has a crucial role in alcohol metabolism. Even though polymorphisms in ADH isoenzyme have been described, they do not appear to be linked to a particular alcohol-related disease or change in alcohol metabolism. However, some researchers have reported that alcohol is eliminated more slowly in the fasted state than in the fed state because of decreased ADH levels (Cederbaum 2012).