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Introduction

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High-Yield Terms

  • Alcohol dehydrogenase (ADH): any of a family of enzymes that catalyze the interconversion of alcohols and aldehydes or ketones; humans express multiple forms of ADH from at least 7 distinct genes

  • Aldehyde dehydrogenase (ALDH): any of a family of enzymes that catalyze the oxidation of aldehydes, 2 primary enzymes, ALDH1A1 and ALDH2, involved in metabolizing acetaldehyde generated during ethanol oxidation

  • Microsomal ethanol-oxidizing system: inducible ethanol-metabolizing system employing a cytochrome P450 enzyme (CYP2E1)

  • Hepatic steatosis: condition of fatty liver that can result from excess alcohol consumption

  • Nonalcoholic fatty liver disease (NAFLD): one cause of a fatty liver (steatosis) not due to excessive alcohol use, most common form of chronic liver disease; obesity and activation of CYP2E1 are major contributors to development of NAFLD and NASH

  • Nonalcoholic steatohepatitis (NASH): progression of NAFLD to state of inflammation and fibrosis, the major feature in NASH is fat in the liver, along with inflammation and cellular damage; obesity and activation of CYP2E1 are major contributors to development of NAFLD and NASH

  • Kupffer cell: liver resident macrophages that contribute to inflammatory responses in response to increased reactive oxygen species generation during ethanol metabolism

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High-Yield Concept

It should be pointed out that humans evolved to express multiple ADH genes and isoforms, not for metabolism of ethanol, but to metabolize naturally occurring alcohols found in foods as well as those produced by intestinal bacteria. As an example, one form of ADH (encoded by the ADH7 gene) is responsible for the metabolism of not only ethanol but also retinol to retinaldehyde, which is the form of vitamin A necessary for vision.

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Ethanol-Metabolizing Pathways

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Ethanol is a small 2-carbon alcohol that, due to its small size and alcoholic hydroxyl group, is soluble in both aqueous and lipid environments. This allows ethanol to freely pass from body fluids into cells. Since the portal circulation from the gut passes first through the liver, the bulk of ingested alcohol is metabolized in the liver. The process of ethanol oxidation involves at least 3 distinct enzymatic pathways. The most significant pathway, responsible for the bulk of ethanol metabolism, is that initiated by alcohol dehydrogenase, ADH. ADH is an NAD+-requiring enzyme expressed at high concentrations in hepatocytes. Animal cells (primarily hepatocytes) contain cytosolic ADH, which oxidizes ethanol to acetaldehyde. Acetaldehyde then enters the mitochondria where it is oxidized to acetate by one of several aldehyde dehydrogenases (ALDHs). A cytosolic ALDH exists but is responsible for only a minor amount of acetaldehyde oxidation.

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The second major pathway for ethanol metabolism is the microsomal ethanol-oxidizing system (MEOS), which involves the NADPH-dependent cytochrome P450 enzyme, CYP2E1. The MEOS pathway is induced in individuals who chronically consume alcohol.

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The third pathway involves a nonoxidative pathway catalyzed by fatty acid ethyl ester (FAEE) synthase. This latter pathway results in the formation of fatty acid ethyl esters and takes place primarily in the ...

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