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.
Alcohol and Aldehyde Dehydrogenases in the Gastrointestinal Tract
Victor R. Preedy, Ronald R. Watson in Alcohol and the Gastrointestinal Tract, 2017
The existence of ethanol metabolism in the gastrointestinal tract depends on the presence of suitable enzymatic systems to oxidize the alcohol to aldehyde. These systems are the microsomal cytochrome P-450 dependent system, catalase, and alcohol dehydrogenase. These three systems exist in the gastrointestinal tract, although their relative contribution is still controversial. Recently, different levels of alcohol dehydrogenase activity and different enzyme forms in the various digestive organs have been described, suggesting that they can be sites of active ethanol oxidation. The second step in ethanol metabolism, the oxidation of acetaldehyde to acetic acid, can be also locally performed due to the presence of aldehyde dehydrogenase in the gastrointestinal tract. This chapter describes the functional and structural characteristics of the gastrointestinal forms of both dehydrogenases and their distribution in human gut. Data from the rat species are also included where the corresponding information from the human enzyme is not available.
The Rational Use of Dietary Supplements, Nutraceuticals, and Functional Foods for the Diabetic and Prediabetic Patient
Jeffrey I. Mechanick, Elise M. Brett in Nutritional Strategies for the Diabetic & Prediabetic Patient, 2006
Alcohol is not stored in the body and its oxidation by alcohol dehydrogenase (ADH), microsomal ethanol oxidizing system (MEOS), and to a lesser extent, catalase, is prioritized over carbohydate and fat oxidation [121]. Alcohol dehydrogenase oxidizes ethanol to acetaldehyde and nicotinamide adenine dinucleotide, reduced form (NADH). Excess NADH participates in the following three pathways: (1) diverts pyruvate into lactic acid formation and away from gluconeogenesis, thus predisposing the person to hypoglycemia; (2) synthesizes glycerol and fatty acids (lipogenesis), thus increasing adiposity; and (3) utilization in mitochondrial electron transport chain for the formation of 5-adenosine tiphosphate (ATP)—but this inhibits fatty acid oxidation, thus increasing ketosis, hepatic fat accumulation, and hyperlipidemia. Acetaldehyde also impairs hepatic mitochondrial function, leading to hepatitis and cirrhosis, and affects central neurotransmitter physiology, leading to addiction. Certain polymorphisms that inactivate aldehyde dehydrogenase-2 (ALDH2), which metabolizes acetaldehyde into acetate, exacerbate these deleterious effects of acetaldehyde. This polymorphism can be detected with genetic testing, and affected persons should avoid alcohol. Excess acetate production further impairs fatty acid oxidation and fat mobilization from adipose tissue, and thus promotes obesity.
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.
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.
Ethnopharmacology†
Published in Nordic Journal of Psychiatry, 2018
David M. Taylor, Ursula Werneke
A somewhat better developed aspect of pharmacogenetics is the study of the role of genetic variation in cytochrome function and its relationship to drug dosing and response [1–3]. Cytochromes and other phase I enzymes (alcohol dehydrogenase, aldehyde dehydrogenase, etc.) are usually found in the liver but also function in the gut wall and in the brain. The speed with which cytochrome enzymes catalyse reactions (and therefore rate of metabolism) is genetically determined. In poor metabolisers, drug metabolism is slowed down. Thus, poor metabolizers are more prone to adverse effects. Slower conversion to active metabolites can potentially also lower efficacy. In rapid metabolisers, drug metabolism is accelerated. Thus, drug elimination rates are increases, and rapid metabolizers may need higher doses to achieve efficacy. The table below shows the relative frequency of poor and ultra-rapid metabolisers by CYP2D6 in different ethnic groups [14] (Table 1). As most SSRIs and many antipsychotics, including risperidone and aripiprazole are substrates of CYP 2D6, a higher proportion of patients from African or Middle Eastern background may experience lower drug efficacy and require dose increases.