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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
The microsomal ethanol oxidizing system constitutes part of the drug metabolizing enzymes which detoxify drugs.350,351,408 Normally, this system is capable of metabolizing and eliminating many drugs including barbiturates. This finding offers an explanation for the resistance of many alcoholics to drugs. However, upon excessive alcohol intake, the drug metabolizing system is utilized for the elimination of the alcohol overload, thus the ability to metabolize barbiturates is exhausted. This fact may explain the increased susceptibility of alcohol addicts to anesthetics and other drugs in the drunken state.
The liver, gallbladder and pancreas
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Dina G. Tiniakos, Alastair D. Burt
Habitual alcohol intake induces the microsomal ethanol oxidizing system (particularly the cytochrome P450 CYP2E1). This, in addition to alcohol dehydrogenases, produces acetaldehyde and depletes the cell of nicotinamide adenosine dinucleotide phosphate (reduced form) (NADPH). These changes directly cause triglyceride accumulation, leading to fatty change as well as cell death. The inflammatory response to cell death includes cytokine production which triggers hepatic stellate cells to synthesize collagen.
Alcohol
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
The pathogenesis of many of the effects of ethanol on lipids, drug, and intermediary metabolism has now been elucidated: these changes are either mediated by metabolites of alcohol, such as acetaldehyde and acetate, or are the result of hepatic generation of NADH (when ethanol is metabolized by hepatic ADH), or are closely similar to processes of microsomal drug detoxification in the liver upon oxidation of ethanol via a new pathway, the microsomal ethanol oxidizing system (MEOS). These effects of ethanol enable us to understand the development of fatty liver, hyperlipemia, hyperlactacidemia, hyperuricemia, ketosis, acidosis, hypoglycemia, metabolic tolerance to ethanol, increased tolerance to drugs in the alcoholic (when sober), and enhanced susceptibility to sedatives and tranquilizers in inebriated individuals. The pathogenesis of ethanol dependence is still not understood but several theoretical mechanisms have been proposed.
High alcohol-producing Klebsiella pneumoniae causes fatty liver disease through 2,3-butanediol fermentation pathway in vivo
Published in Gut Microbes, 2021
Nan-Nan Li, Wei Li, Jun-Xia Feng, Bing Du, Rui Zhang, Shu-Heng Du, Shi-Yu Liu, Guan-Hua Xue, Chao Yan, Jing-Hua Cui, Han-Qing Zhao, Yan-Ling Feng, Lin Gan, Qun Zhang, Wei-Wei Zhang, Di Liu, Chen Chen, Jing Yuan
Under normal conditions, ethanol is constantly produced by the intestinal microbiota in the human gut, as increased blood alcohol concentrations were detected after the intake of alcohol-free food,20,21 but the endogenous ethanol is rapidly and almost completely removed from portal blood by liver ADHs, catalases, and the microsomal ethanol-oxidizing system. It remained to be determined whether HiAlc Kpn utilizes the 2,3-butanediol fermentation pathway to produce high-level endogenous alcohol in vivo, which would be different from the alcohol-production pathway used by yeast. Considering all of the potential alcohol-producing pathways in bacteria, we found that the majority of the enriched proteins and metabolites were associated with the 2,3-butanediol fermentation pathway (Figure 4d), which is a neglected pathway for alcohol production from glucose and glycerol metabolism in vivo. Accordingly, the key upregulated enzymes and metabolites all belonged to this pathway (Figure 4d). On the one hand, the pathway is capable of efficiently transforming sugar and glycerol into alcohols and acids. On the other hand, the metabolites derived from alcohol catabolism, including acetaldehyde, acetic acid and fatty acid ethyl esters, may also cause tissue injury and hepatic steatosis.
Molecular mechanisms of ethanol biotransformation: enzymes of oxidative and nonoxidative metabolic pathways in human
Published in Xenobiotica, 2020
Grażyna Kubiak-Tomaszewska, Piotr Tomaszewski, Jan Pachecka, Marta Struga, Wioletta Olejarz, Magdalena Mielczarek-Puta, Grażyna Nowicka
A number of toxic effects of ethanol result not only from its direct impact on the body constituents, but is the result of the action of toxic metabolites formed during its biotransformation. Acetaldehyde formed during the aerobic metabolism of ethanol with the help of alcohol dehydrogenase (ADH), microsomal ethanol oxidizing system (MEOS) or, to a much lesser extent by hepatic catalase (CAT), plays a special role here. Acetaldehyde corresponds to, among others for the development of alcoholic liver disease (ALD), which is a sequence of alcoholic hepatitis, alcoholic cirrhosis (AC) and hepatocellular carcinoma (HCC). By-products of ethanol oxidation, such as oxygen free radicals (ROS), are also dangerous (Teschke, 2018). Also products of non-oxidative ethanol metabolism may be toxic. For example, fatty acid ethyl ester (FAEE) has been shown to be responsible for pancreatic acinar cell injury and myocardial damage (Laposata et al., 2002). Important for clinical and diagnostic reason is also the polymorphism of enzymes involved in ethanol biotransformation, as it determines not only the efficiency of metabolic processes, but also its organ specificity.
Aldehyde dehydrogenase-2 as a therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2019
Mitsuru Kimura, Akira Yokoyama, Susumu Higuchi
Aldehyde dehydrogenase-2 (ALDH2) plays a critical role in alcohol metabolism. Ethanol consumed by the body is first metabolized in the liver by alcohol dehydrogenase (ADH), microsomal ethanol oxidizing system (MEOS), and catalase to form acetaldehyde, and consequently oxidized to acetic acid by aldehyde dehydrogenase (ALDH). Nineteen genes belonging to the ALDH gene superfamily have been identified [1]. The isozymes belonging to ALDH superfamily play important roles in homeostasis and survival. For example, ALDH1A subfamily is necessary for embryogenesis due to its ability of retinoic-acid synthesis [2,3]. The enzyme ALDH2 is widely distributed in the cellular mitochondrial matrix in many organs of the body, and is particularly abundant in the liver. The highest affinity of ALDH2 is observed for acetaldehyde, which is mainly responsible for execution of the second step in the process of ethanol elimination [4]. The expressed ALDH2 monomers work by forming a tetramer, which occurs as a pair of dimers [5].