Food Types, Dietary Supplements, and Roles
Chuong Pham-Huy, Bruno Pham Huy in Food and Lifestyle in Health and Disease, 2022
The balance between the various ADH and ALDH isoforms regulates the concentration of acetaldehyde, which is important as a key risk factor for the development of alcoholism (49–50). Acetaldehyde dehydrogenase 2 (ALDH2) is the key enzyme responsible for metabolism of the alcohol metabolite acetaldehyde in the liver (49). Certain individuals, usually of Asian origin (China, Japan, Korea, Vietnam), have an inactive mitochondrial ALDH2 because of a genetic ALDH deficiency. Of note, approximately 8% of the world’s population, and approximately 30–40% of the population in East Asia, carry an inactive ALDH2 gene (49). Thus, when these individuals consume ethanol, blood levels of acetaldehyde are 5-to 20-fold higher than those found in individuals with the active ALDH allele. Individuals with the inactive ALDH show marked vasodilator (facial flushing or red face), nausea, headaches, and palpitation when consuming alcohol (50). Acetaldehyde is poorly eliminated by these individuals and as a consequence, little alcohol is consumed. ALDH2 deficient individuals are at lower risk for alcoholism. In contrast, they may have possibly increased risk for liver damage and esophageal cancer if alcohol continues to be consumed due to the accumulation of acetaldehyde in these organs (49–51).
Alcohol Pharmacology and Pharmacotherapy of Alcoholism
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
Alcohol dehydrogenase (ADH) belongs to a family of cytosolic enzymes with zinc, found mostly in the hepatic area, gastrointestinal tract, brain, kidneys, testes, and uterus. It oxidizes exogenously consumed alcohol, endogenous alcohol formed by gut microflora, and also in substrates involved in bile acid/steroid metabolism (Cederbaum, 2012). ADH enzyme in presence of nicotinamide adenine dinucleotide (NAD) as a cofactor brings about the transformation of alcohol to acetaldehyde. Genetic variations in these enzymes can modify the degree of alcohol metabolism and hence predispose to individual’s susceptibility to alcohol abuse disorders as described below in Table 17.2. For instance, genetic polymorphism in one ADH allele- ADH1B*2, more common in East Asians leads to hasty transformation of alcohol to acetaldehyde results in protection against alcohol dependence (Suddendorf, 1989). ADH is also present in the stomach and contributes partly to metabolism of alcohol. Women have low levels of gastric enzyme which cause dissimilarities in BAC in men and women (Lieber, 2000; Schuckit, 2006b).
Fetal Alcohol Syndrome
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
One of the proposed genetic susceptibility factors for FAS is the activity of the enzyme alcohol dehydrogenase (ADH), which catalyzes the oxidation of ethanol to acetaldehyde. There are at least four classes of ADH enzymes in humans, of which class I ADH appears to be the most important (19). Class I ADH isoenzymes are heterodimers composed of some combination of either alpha, beta, or gamma subunit chains. The gene which encodes the beta chain, ADH2, has three common alleles, known as ADH2*1, ADH2*2, and ADH2*3. Each of these alleles has a different affinity for alcohol and a different rate of maximum catalysis. McCarver et al. in 1997 (19) proposed that the ADH2*3 allele protected against ARBD in an African-American population, possibly related to its increased catalytic activity. In 2000, Jacobson et al. (20) reported that a group of African-Americans with the ADH2*3 allele drank less amounts of alcohol less frequently than a group of African-Americans without the ADH2*3 allele. Studies on the effects of the ADH2*2 allele have been more controversial, with some studies reporting a protective effect against alcoholism and FAS (21-23) and some studies reporting no effect on alcohol consumption (24). Thus, the role of the alleles of ADH2 in susceptibility remains controversial.
Recent developments in predicting CYP-independent metabolism
Published in Drug Metabolism Reviews, 2021
Nikhilesh V. Dhuria, Bianka Haro, Amit Kapadia, Khadjia A. Lobo, Bernice Matusow, Mary A. Schleiff, Christina Tantoy, Jasleen K. Sodhi
The involvement of ADH/ALDH in metabolism of recently approved drugs has been noted for a small number of drugs (Cerny 2016; Saravanakumar et al. 2019), as well as in the minor metabolism (Kamel et al. 2012) and major metabolism (Bowers et al. 2013) of relatively recent clinical candidates. An extensive, new review notes that in drug discovery efforts, there are a number of challenges associated with IVIVE of ADH substrates, such as the currently unknown substrate specificity of specific isoforms, the marked species differences in the expression and tissue abundance of ADHs, the potential for induction via the nuclear receptor farnesoid X receptor (FXR), and the extrahepatic expression of human ADHs that are inherently difficult to incorporate into IVIVE approaches (Di et al. 2021). The authors further note that they could not identify any examples in the literature on IVIVE for ADH substrates (Di et al. 2021). Based on our survey of the literature, we can confirm the same challenges exist for prediction of ALDH-mediated clearance and limited examples of ADH/ALDH-based IVIVE are available. A recent quantitative proteomic analysis of a large cohort of pediatric and adult livers revealed that neonatal levels of ALD/ALDH were significantly lower than adult levels; however, no differences with respect to ethnicity and sex were observed (Bhatt et al. 2017). These valuable results contribute to our evolving understanding of these enzymes, and we emphasize that further investigations toward characterization of ADH/ALDH are important for the field to pursue.
Boletus aereus protects against acute alcohol-induced liver damage in the C57BL/6 mouse via regulating the oxidative stress-mediated NF-κB pathway
Published in Pharmaceutical Biology, 2020
Luping Zhang, Bo Meng, Lanzhou Li, Yanzhen Wang, Yuanzhu Zhang, Xuexun Fang, Di Wang
AST and ALT serve as biomarkers for liver function, directly reflecting the degree of liver injury. ADH and ALDH are the main enzymes responsible for alcohol metabolism (Kaviarasan and Anuradha 2007). Compared with the healthy mice, extremely high levels of AST (>15.6%) and ALT (>12.9%), and low levels of ADH (23.1%) and ALDH (>14.0%) in the liver and/or serum, were noted in the alcohol-only treated mice (p < 0.05; Table 2). Compared with the alcohol-only treated mice, similar to Sil, BA only strongly enhanced the levels of ALDH (>18.9%) in the serum (p < 0.05; Table 2). In the liver, BA treatment remarkably reduced the levels of AST (>27.6%) and ALT (>18.3%) (p < 0.05; Table 2), and enhanced the levels of ADH (>35.0%) (p < 0.01; Table 2). Sil regulated the levels of AST, ADH and ALDH (p < 0.05; Table 2), but not ALT (p > 0.05; Table 2).
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).
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