Ethanol metabolism

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.

Human metabolic physiologyEdit

Ethanol and evolutionEdit

The average human digestive system produces approximately 3 g of ethanol per day through fermentation of its contents.[1] 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 3.5 bya.[2] Such a function is necessary because all organisms produce alcohol in small amounts by several pathways, primarily through fatty acid synthesis,[3] glycerolipid metabolism,[4] and bile acid biosynthesis pathways.[5] 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.

Physiologic structuresEdit

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 concentration of such enzymes are found in the liver,[6] which is the primary site for alcohol catabolism. Variations in genes influence alcohol metabolism and drinking behavior.[7]

Thermodynamic considerationsEdit

Energy thermodynamicsEdit

Energy calculationsEdit

The reaction from ethanol to carbon dioxide and water is a complex one that proceeds in three steps. Below, the Gibbs free energy of formation for each step is shown with ΔGf values given in the CRC.[8]

Complete reaction:
C2H6O(ethanol) → C2H4O(acetaldehyde) → C2H4O2(acetic acid) → acetyl-CoA → 3H2O + 2CO2.
ΔGf = Σ ΔGfp − ΔGfo

Step oneEdit

C2H6O(ethanol) + NAD+ → C2H4O(acetaldehyde) + NADH + H+
Ethanol: −174.8 kJ/mol
Acetaldehyde: −127.6 kJ/mol
ΔGf1 = −127.6 kJ/mol + 174.8 kJ/mol = 47.2 kJ/mol (endergonic)
ΣΔGf = 47.2 kJ/mol (endergonic, but this does not take into consideration the simultaneous reduction of NAD+.)

Step twoEdit

C2H4O(acetaldehyde) + NAD+ + H2O → C2H4O2(acetic acid) + NADH + H+
Acetaldehyde: −127.6 kJ/mol
Acetic acid: −389.9 kJ/mol
ΔGf2 = −389.9 kJ/mol + 127.6 kJ/mol = −262.3 kJ/mol (exergonic)
ΣΔGf = −262.3 kJ/mol + 47.2 kJ/mol = −215.1 kJ/mol (exergonic, but again this does not take into consideration the reduction of NAD+.)

Step threeEdit

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

(Because the Gibbs energy is a state function, we skip the formation of Acetyl-CoA (step 3), for lack of thermodynamic values.)

For the oxidation of acetic acid we have:
Acetic acid: −389.9 kJ/mol
3H2O + 2CO2: −1500.1 kJ/mol
ΔGf4 = −1500 kJ/mol + 389.6 kJ/mol = −1110.5 kJ/mol (exergonic)
ΣΔGf = −1110.5 kJ/mol215.1 kJ/mol = −1325.6 kJ/mol (exergonic)

Discussion of calculationsEdit

If catabolism of alcohol goes all the way to completion, then, we have a very exothermic event yielding some 1325 kJ/mol 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 215.1 kJ/mol. At the very least, the theoretical limits on energy yield are determined to be −215.1 kJ/mol to −1325.6 kJ/mol. It is also important to note that step 1 on this reaction is endothermic, requiring 47.2 kJ/mol of alcohol, or about 3 molecules of adenosine triphosphate (ATP) per molecule of ethanol.

Organic reaction schemeEdit

Steps of the reactionEdit

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 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 is believed to at least largely underlie the pathogenesis of alcoholic fatty liver disease.

Gene expression and ethanol metabolismEdit

Ethanol to acetaldehyde in human adultsEdit

In human adults, ethanol is oxidized to acetaldehyde using NAD+, mainly via the hepatic enzyme alcohol dehydrogenase IB (class I), beta polypeptide (ADH1B, EC The gene coding for this enzyme is located on chromosome 4, locus.[9] 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, other aliphatic alcohols, hydroxysteroids, 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.[10]

Ethanol to acetaldehyde in human fetusesEdit

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).[11] 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.[12] CYP2E1 expression and activity have been detected in various human fetal tissues after the onset of organogenesis (ca 50 days of gestation).[13] 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 (MEOS)[14] and its activity in fetal tissues is thought to contribute significantly to the toxicity of maternal ethanol consumption.[11][15] In presence of ethanol and oxygen, CYP2E1 is known[by whom?] to release superoxide radicals and induce the oxidation of polyunsaturated fatty acids to toxic aldehyde products like 4-hydroxynonenal (HNE).[citation needed]

Acetaldehyde to acetic acidEdit

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 such as ascorbic acid (vitamin C) or thiamine (vitamin B1). 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.[16] 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 2 family (ALDH2, EC In humans, the gene coding for this enzyme is found on chromosome 12, locus q24.2.[17] There is variation in this gene leading to observable differences in catalytic efficiency between people.[18]

Acetic acid to acetyl-CoAEdit

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[19] The second enzyme is acetyl-CoA synthase 2 (confusingly also called ACSS1) which is localized in mitochondria.

Acetyl-CoA to water and carbon dioxideEdit

Once acetyl-CoA is formed, it enters the normal citric acid cycle.

See alsoEdit


  2. ^ group, NIH/NLM/NCBI/IEB/CDD. "NCBI CDD Conserved Protein Domain ADH_zinc_N". Retrieved 2018-04-28.
  3. ^ "Fatty Acid Synthesis".
  4. ^ "Glycerolipid Metabolism".
  5. ^ "Bile Acid Biosynthesis".
  6. ^ Tanaka, Furnika; Shiratori, Yasushi; Yokosuka, Osarnu; Imazeki, Furnio; Tsukada, Yoshio; Omata, Masao (June 1997). "Polymorphism of Alcohol-Metabolizing Genes Affects Drinking Behavior and Alcoholic Liver Disease in Japanese Men". Alcoholism: Clinical and Experimental Research. 21 (4): 596–601. doi:10.1111/j.1530-0277.1997.tb03808.x. PMID 9194910.
  7. ^ Agarwal, D.P (Nov 2001). "Genetic polymorphisms of alcohol metabolizing enzymes". Pathol Biol (Paris). 49 (9): 703–9. doi:10.1016/s0369-8114(01)00242-5. PMID 11762132.
  8. ^ CRC Handbook of Chemistry and Physics, 81st Edition, 2000
  9. ^ 4q21-q23
  10. ^ "ADH1B alcohol dehydrogenase 1B (class I), beta polypeptide [Homo sapiens (human)] - Gene - NCBI". Retrieved 2018-04-28.
  11. ^ a b Ernst van Faassen and Onni Niemelä, Biochemistry of prenatal alcohol exposure, NOVA Science Publishers, New York 2011.[page needed]
  12. ^ Nava-Ocampo, Alejandro A.; Velázquez-Armenta, Yadira; Brien, James F.; Koren, Gideon (June 2004). "Elimination kinetics of ethanol in pregnant women". Reproductive Toxicology. 18 (4): 613–617. doi:10.1016/j.reprotox.2004.02.012. PMID 15135856.
  13. ^ Brzezinski, Monica R.; Boutelet-Bochan, Helene; Person, Richard E.; Fantel, Alan G.; Juchau, Mont R. (1 June 1999). "Catalytic Activity and Quantitation of Cytochrome P-450 2E1 in Prenatal Human Brain". Journal of Pharmacology and Experimental Therapeutics. 289 (3): 1648–1653. PMID 10336564.
  14. ^ Lieber, Charles S. (25 October 2004). "The Discovery of the Microsomal Ethanol Oxidizing System and Its Physiologic and Pathologic Role". Drug Metabolism Reviews. 36 (3–4): 511–529. doi:10.1081/dmr-200033441. PMID 15554233. S2CID 27992318.
  15. ^ Pregnancy and Alcohol Consumption, ed. J.D. Hoffmann, NOVA Science Publishers, New York 2011.[page needed]
  16. ^ "Acetaldehyde" (PDF). Archived (PDF) from the original on 2010-06-05. Retrieved 2010-04-11.
  17. ^ "Homo sapiens chromosome 12, reference assembly, complete sequence - Nucleotide - NCBI". Retrieved 2018-04-28.
  18. ^ "ALDH2 aldehyde dehydrogenase 2 family member [Homo sapiens (human)] - Gene - NCBI". Retrieved 2018-04-28.
  19. ^ "ACSS2 acyl-CoA synthetase short chain family member 2 [Homo sapiens (human)] - Gene - NCBI". Retrieved 2018-04-28.

Further readingEdit