Characteristics and Theories Related to Acute and Chronic Tolerance Development
S.J. Mulé, Henry Brill in Chemical and Biological Aspects of Drug Dependence, 2019
The biochemical basis of the augmentation of ethanol metabolism is not totally clear. First of all, there is uncertainty as to the rate limiting factor in ethanol metabolism; both limited alcohol dehydrogenase and a limited rate of reoxidation of reduced nicotinamide adenine dinucleotide phosphate108,347 (formed during alcohol oxidation) have been suggested. Secondly, some authors have associated ethanol tolerance with increased activity of hepatic enzymes (alcohol dehydrogenase, catalase, microsomal oxidases) while others have denied a cause-effect relationship. (See reviews210,244,347,348 for details and critical analyses.) Finally, it must be recognized that a number of factors influence the rate of ethanol metabolism in vivo and in vitro, and that in vitro experiments are subject to the introduction of artifacts and may not be representative of what is occurring in the intact organism.
Alcoholic Pancreatitis
Victor R. Preedy, Ronald R. Watson in Alcohol and the Gastrointestinal Tract, 2017
Under conditions of low to moderate ethanol intake, ethanol is primarily oxidized to acetaldehyde via alcohol dehydrogenase. At higher levels of ethanol consumption, another microsomal enzyme system is induced which becomes a major pathway of ethanol metabolism in heavy drinkers. Originally termed the microsomal ethanol oxidizing system (MEOS), it is now clear that this is almost entirely due to a single form of cytochrome P-450 (CYP) termed CYP2E1182 ("cytochrome P-450" is actually a superfamily of over 300 enzymes, of which CYP2E1 is one). In the process of catalyzing the oxidation of ethanol to acetaldehyde, CYP2E1 generates toxic oxygen species such as hydrogen peroxide and hydroxyl radicals. Usually, these compounds are rapidly metabolized by enzymes or inactivated by free radical scavengers.
Alcohol-Induced Hepatotoxicity
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
Only 2–10% of the ethanol absorbed is eliminated through the kidneys and lungs. The rest must be oxidized in the body, principally in the liver, which contains the bulk of the body’s enzymes capable of ethanol oxidation. This relative organ specificity probably explains why ethanol oxidation produces striking metabolic imbalances in the liver. These effects are aggravated by the lack of feedback mechanism to adjust the rate of ethanol oxidation to the metabolic state of the hepatocyte, and the inability of ethanol, unlike other major sources of calories, to be stored or metabolized to a significant degree in peripheral tissues. When ethanol is present, it becomes the preferred fuel for the liver. By displacing up to 90% of all other substrates normally utilized by the liver (Lundquist and co-workers, 1962), ethanol literally takes over the intermediary metabolism of the liver. Ethanol metabolism in the liver results in the production of hydrogen and acetaldehyde (Figure 2). Each of these two products is directly responsible for a variety of metabolic alterations that play a role in the development of liver injury. A link between hepatotoxicity of ethanol and its metabolism could also explain some of the zonal changes in alcoholic liver disease (vide infra).
Melatonin modulates oxidative phosphorylation, hepatic and kidney autophagy-caused subclinical endotoxemia and acute ethanol-induced oxidative stress
Published in Chronobiology International, 2020
Natalia Kurhaluk, Halyna Tkachenko, Oleksandr Lukash
The current study demonstrated a different course of ethanol-induced toxicity, subclinical endotoxemia caused by LPS-induced inflammation, and effects of Mel treatment in kidney and liver, as these organs are the principal sites of ethanol metabolism. The liver is the primary organ responsible for the oxidation of ethanol. On the other hand, the kidney is involved in ethanol metabolism as well. The data of the current study revealed that ethanol enhanced fatty acid oxidation in kidney microsomes and peroxisomes and affected activities of some kidney lysosomal hydrolases. Currently, there are no conclusive published data that defines the relationship between oxygen consumption, activities of lysosomal enzymes, and antioxidant defenses in these organs exposed to ethanol, subclinical LPS-induced endotoxemia, and Mel treatment.
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
The microsomal pathway (involving the cytochrome P450 (CYP) family) is responsible for about 10% of the body’s ethanol metabolism (Hamitouche et al. 2006). Even though CYP1A2 and CYP3A4 are known to be involved, CYP2E1 is considered to be the main CYP in the first phase of ethanol metabolism (Kunitoh et al. 1996; Cederbaum 2012). This oxidative metabolic pathway takes place in the endoplasmic reticulum of hepatocytes. Using NADPH and oxygen, CYP2E1 converts ethanol into acetaldehyde and then acetaldehyde into acetate. The conversion of ethanol into acetaldehyde produces reactive oxygen species (ROS), which notably contribute to alcohol’s toxicity (Ekström and Ingelman-Sundberg 1989). Furthermore, ethanol upregulates its own metabolism by protecting CYP2E1 from ubiquitination and degradation by the proteasome complex (Zhukov and Ingelman-Sundberg 1999; Lu and Cederbaum 2008). This mechanism results in elevated levels of CYP2E1 in hepatocytes, and is considered to have a major role in the ethanol tolerance seen in chronic alcohol users (Cederbaum 2012).
Characterization of oral microbiota and acetaldehyde production
Published in Journal of Oral Microbiology, 2018
Shigeyuki Yokoyama, Kenji Takeuchi, Yukie Shibata, Shinya Kageyama, Rie Matsumi, Toru Takeshita, Yoshihisa Yamashita
Acetaldehyde (ACH), the first metabolite produced during ethanol metabolism, is a carcinogen found in the oral cavity [1]. Recently, ACH production associated with the consumption of alcoholic beverages has been reclassified as highly carcinogenic (Group 1) by the International Agency for Research on Cancer of the World Health Organization [2]. In particular, increased ACH levels in saliva have been associated with increased risk for upper aerodigestive tract cancer [3–5], which was the seventh most common cancer in Japan in 2011 with one million newly diagnosed cases annually worldwide [6,7]. Increased ACH levels in saliva after ethanol consumption are suggested to be due to oxidation of alcohol by the oral microbiota [8,9].