Alcohol Metabolism

 Alcohol Metabolism

Introduction

Ethanol, an alcohol found in nature and in alcoholic drinks, is metabolized through a complex catabolic metabolic pathway. In humans, several enzymes are involved in processing ethanol first into acetaldehyde and further into acetic acid and acetyl-CoA. Once acetyl-CoA is formed, it becomes a substrate for the citric acid cycle ultimately producing cellular energy and releasing water and carbon dioxide.

Due to differences in enzyme presence and availability, human adults and fetuses process ethanol through different pathways. Gene variation in these enzymes can lead to variation in catalytic efficiency between individuals. The liver is the major organ that metabolizes ethanol due to its high concentration of these enzymes.

The average human digestive system produces approximately 3 g of ethanol per day through fermentation of its contents. Catabolic degradation of ethanol is thus essential to human life. Such a function is necessary because all organisms produce alcohol in small amounts by several pathways, primarily through fatty acid synthesis, glycerolipid metabolism, and bile acid biosynthesis pathways. If the body had no mechanism for catabolizing the alcohols, they would build up in the body and become toxic

Steps

The reaction from ethanol to carbon dioxide and water is a complex one that proceeds in at least 11 steps in humans.

Complete Reaction

C₂H₆O(ethanol) → C₂H₄O(acetaldehyde) → C₂H₄O₂(acetic acid) → acetyl-CoA → 3H₂O+2CO₂.

Step 1

C₂H₆O(ethanol) + NAD⁺ → C₂H₄O(acetaldehyde) + NADH + H⁺

Ethanol is oxidized to acetaldehyde using NAD⁺, mainly via the hepatic enzyme alcohol dehydrogenase.

Step 2

C₂H₄O(acetaldehyde) + NAD⁺ + H₂O → C₂H₄O₂(acetic acid) + NADH + H⁺

The enzyme associated with the chemical transformation from acetaldehyde to acetic acid is aldehyde dehydrogenase

Step 3

C₂H₄O₂(acetic acid) + CoA + ATP → Acetyl-CoA + AMP + PP_i

 

Two enzymes are associated with the conversion of acetic acid to acetyl-CoA. The first is acyl-CoA synthetase. The second enzyme is acetyl-CoA synthase 2 which is localized in mitochondria.

Steps 4 through 11

After this the acetyl-CoA enters the TCA cycle and is converted to 2 CO₂  molecules in 8 reactions with the help of its enzyme system.

The first three steps of the reaction pathways lead from ethanol to acetaldehyde to acetic acid to acetyl-CoA. Once acetyl-CoA is formed, it is free to enter directly into the citric acid cycle.

However, under alcoholic conditions, the citric acid cycle has been stalled by the oversupply of NADH derived from ethanol oxidation. The resulting backup of acetate shifts the reaction equilibrium for acetaldehyde dehydrogenase back towards acetaldehyde.  

Acetaldehyde subsequently accumulates and begins to form covalent bonds with cellular macromolecules, forming toxic compounds that, eventually, lead to death of the cell. This same excess of NADH from ethanol oxidation causes the liver to move away from fatty acid oxidation, which produces NADH, towards fatty acid synthesis, which consumes NADH. This consequent lipogenesis is responsible for the pathogenesis of alcoholic fatty liver disease.