Ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

, an alcohol found in

nature Nature, in the broadest sense, is the physical world or universe. "Nature" can refer to the phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. Although humans are ...

and in

alcoholic drink An alcoholic beverage (also called an alcoholic drink, adult beverage, or a drink) is a drink that contains ethanol, a type of alcohol that acts as a drug and is produced by fermentation of grains, fruits, or other sources of sugar. The c ...

s, is

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

through a complex

catabolic Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipid ...

metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...

. 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 The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...

ultimately producing cellular energy and releasing water and

carbon dioxide Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is trans ...

. 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.

Human metabolic physiology

Ethanol and evolution

The average human digestive system produces approximately 3g of ethanol per day through fermentation of its contents. Catabolic degradation of ethanol is thus essential to life, not only of humans, but of all known organisms. Certain amino acid sequences in the enzymes used to oxidize ethanol are conserved (unchanged) going back to the last common ancestor over 3.5bya. Such a function is necessary because all organisms produce alcohol in small amounts by several pathways, primarily through

fatty acid synthesis In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is co ...

glycerolipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include s ...

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. This could be an evolutionary rationale for alcohol catabolism also by

sulfotransferase Sulfotransferases (SULTs) are transferase enzymes that catalyze the transfer of a sulfo group from a donor molecule to an acceptor alcohol or amine. The most common sulfo group donor is 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In the case o ...

Physiologic structures

A basic organizing theme in biological systems is that increasing complexity in specialized tissues and organs allows for greater specificity of function. This occurs for the processing of ethanol in the human body. The enzymes required for the oxidation reactions are confined to certain tissues. In particular, much higher concentrations of such enzymes are found in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

, which is the primary site for alcohol catabolism. Variations in genes influence alcohol metabolism and drinking behavior.

Thermodynamic considerations

Energy thermodynamics

Energy calculations

The reaction from ethanol to

and

water Water (chemical formula ) is an Inorganic compound, inorganic, transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living ...

is a complex one that proceeds in at least 11 steps in humans. Below, the

Gibbs free energy In thermodynamics, the Gibbs free energy (or Gibbs energy; symbol G) is a thermodynamic potential that can be used to calculate the maximum amount of work that may be performed by a thermodynamically closed system at constant temperature and ...

of formation for each step is shown with ΔG_f values given in the CRC. Complete reaction:
C₂H₆O(ethanol) → C₂H₄O(acetaldehyde) → C₂H₄O₂(acetic acid) → acetyl-CoA → 3H₂O + 2CO₂.
ΔG_f = Σ ΔG_fp − ΔG_fo

=Step one

= C₂H₆O(ethanol) + NAD⁺ → C₂H₄O(acetaldehyde) +

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...

+ H⁺
Ethanol:
Acetaldehyde:
ΔG_f1 = + = (endergonic)
ΣΔG_f = (endergonic, but this does not take into consideration the simultaneous reduction of NAD⁺.)

=Step two

= C₂H₄O(acetaldehyde) + NAD⁺ + H₂O → C₂H₄O₂(acetic acid) +

+ H⁺
Acetaldehyde:
Acetic acid:
ΔG_f2 = + = (exergonic)
ΣΔG_f = + = (exergonic, but again this does not take into consideration the reduction of NAD⁺.)

=Step three

= C₂H₄O₂(acetic acid) + CoA + ATP → Acetyl-CoA + AMP + PP_i ΔG_f3 =

=Steps 4 through 11

= After this the acetyl-CoA enters the TCA cycle and is converted to 2 CO₂ molecules in 8 reactions. Because the Gibbs energy is a state function, we can ignore all of these, and indeed can ignore even the above 3 reactions. Overall, the free energy is simply calculated from the free energy of formation of the product and reactants. For the oxidation of acetic acid we have:
Acetic acid:
3H₂O + 2CO₂:
ΔG_f4 = + = (exergonic)
ΣΔG_f = − = (exergonic)

Discussion of calculations

If catabolism of alcohol goes all the way to completion, then we have a very exothermic event yielding some of energy. If the reaction stops part way through the metabolic pathways, which happens because acetic acid is excreted in the urine after drinking, then not nearly as much energy can be derived from alcohol, indeed, only . At the very least, the theoretical limits on energy yield are determined to be to . It is also important to note that step 1 on this reaction is endothermic, requiring of alcohol, or about 3 molecules of

adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms o ...

(ATP) per molecule of ethanol.

Organic reaction scheme

Steps of the reaction

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

. 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 Acetaldehyde dehydrogenases () are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetic acid. The oxidation of acetaldehyde to acetate can be summarized as follows: Acetaldehyde + NAD+ + Coenzyme A ↔ Acetyl-CoA + NA ...

back towards acetaldehyde. Acetaldehyde subsequently accumulates and begins to form covalent bonds with cellular macromolecules, forming toxic adducts 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 In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride syn ...

is believed to account largely for the pathogenesis of alcoholic fatty liver disease.

Gene expression and ethanol metabolism

Ethanol to acetaldehyde in human adults

In human adults, ethanol is oxidized to acetaldehyde using NAD⁺, mainly via the hepatic enzyme

alcohol dehydrogenase Alcohol dehydrogenases (ADH) () are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to NA ...

IB (class I), beta polypeptide (ADH1B, EC 1.1.1.1). The gene coding for this enzyme is located on chromosome 4, locus. The enzyme encoded by this gene is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol,

retinol Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family found in food and used as a dietary supplement. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xeroph ...

, other aliphatic alcohols,

hydroxysteroid A hydroxysteroid is a molecule derived from a steroid with a hydrogen replaced with a hydroxy group. When the hydroxy group is specifically at the C3 position, hydroxysteroids are referred to as sterols, with an example being cholesterol. See a ...

s, and lipid peroxidation products. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster. CYP2E1, another enzyme involved in ethanol oxidation, is upregulated by ethanol exposure, meaning that ethanol is capable of inducing its own metabolism. Ethanol has indeed been observed to be cleared more quickly by regular drinkers than non-drinkers.

Ethanol to acetaldehyde in human fetuses

In human embryos and fetuses, ethanol is not metabolized via this mechanism as ADH enzymes are not yet expressed to any significant quantity in human fetal liver (the induction of ADH only starts after birth, and requires years to reach adult levels).Ernst van Faassen and Onni Niemelä, Biochemistry of prenatal alcohol exposure, NOVA Science Publishers, New York 2011. Accordingly, the fetal liver cannot metabolize ethanol or other low molecular weight xenobiotics. In fetuses, ethanol is instead metabolized at much slower rates by different enzymes from the cytochrome P-450 superfamily (CYP), in particular by CYP2E1. The low fetal rate of ethanol clearance is responsible for the important observation that the fetal compartment retains high levels of ethanol long after ethanol has been cleared from the maternal circulation by the adult ADH activity in the maternal liver. CYP2E1 expression and activity have been detected in various human fetal tissues after the onset of organogenesis (ca 50 days of gestation). Exposure to ethanol is known to promote further induction of this enzyme in fetal and adult tissues. CYP2E1 is a major contributor to the so-called

Microsomal Ethanol Oxidizing System {{other uses, Meos (disambiguation) The microsomal ethanol oxidizing system (MEOS) is an alternate pathway of ethanol metabolism that occurs in the smooth endoplasmic reticulum in the oxidation of ethanol to acetaldehyde. While playing only a mino ...

(MEOS) and its activity in fetal tissues is thought to contribute significantly to the toxicity of maternal ethanol consumption. In presence of ethanol and oxygen, CYP2E1 is known to release superoxide radicals and induce the oxidation of polyunsaturated fatty acids to toxic aldehyde products like 4-hydroxynonenal (HNE).

Acetaldehyde to acetic acid

At this point in the metabolic process, the ACS alcohol point system is utilized. It standardizes ethanol concentration regardless of volume, based on fermentation and reaction coordinates, cascading through the β-1,6 linkage. Acetaldehyde is a highly unstable compound and quickly forms free radical structures which are highly toxic if not quenched by

antioxidants Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants, ...

such as ascorbic acid (

vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...

) or thiamine (

vitamin B1 Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thia ...

). These free radicals can result in damage to embryonic neural crest cells and can lead to severe birth defects. Prolonged exposure of the kidney and liver to these compounds in chronic alcoholics can lead to severe damage. The literature also suggests that these toxins may have a hand in causing some of the ill effects associated with hang-overs. The enzyme associated with the chemical transformation from acetaldehyde to acetic acid is

aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have b ...

2 family (

ALDH2 Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ''ALDH2'' gene located on chromosome 12. This protein belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the ...

, EC 1.2.1.3). In humans, the gene coding for this enzyme is found on chromosome 12, locus q24.2. There is variation in this gene leading to observable differences in catalytic efficiency between people.

Acetic acid to acetyl-CoA

Two enzymes are associated with the conversion of acetic acid to acetyl-CoA. The first is acyl-CoA synthetase short-chain family member 2 ACSS2 (EC 6.2.1.1). The second enzyme is acetyl-CoA synthase 2 (confusingly also called ACSS1) which is localized in mitochondria.

Acetyl-CoA to water and carbon dioxide

Once acetyl-CoA is formed, it enters the normal