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Pharmacology of ethanol#Metabolism

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+#REDIRECT [[Pharmacology of ethanol#Metabolism]]
-{{Original research|article|date=January 2008}}
+{{R from merge}}
-[[Ethanol]], an [[Alcohol (chemistry)|alcohol]] found in [[nature]] and in [[alcoholic drink]]s, 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 physiology==
-===Ethanol and evolution===
-The average human digestive system produces approximately 3{{nbsp}}g of ethanol per day through fermentation of its contents.<ref>[https://helda.helsinki.fi/bitstream/handle/10138/22713/ethanola.pdf?sequence=2 ETHANOL, ACETALDEHYDE AND GASTROINTESTINAL FLORA] Jyrki Tillonen {{ISBN|952-91-2603-4}} PDF</ref> 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{{nbsp}}bya.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?ascbin=8&maxaln=10&seltype=3&uid=pfam00107&querygi=34577061&aln=12,1,15,46,49,61,57,106,139,51,157,191,53,210,245,16,227,261,10,237,273,39,277,312,15,292,329,11,304,340,11,316,351,16,333,367,8|title=NCBI CDD Conserved Protein Domain ADH_zinc_N|last=group|first=NIH/NLM/NCBI/IEB/CDD|website=www.ncbi.nlm.nih.gov|language=en|access-date=2018-04-28}}</ref> Such a function is necessary because all organisms produce alcohol in small amounts by several pathways, primarily through [[fatty acid synthesis]],<ref>{{cite web|url=http://www.genome.jp/dbget-bin/show_pathway?hsa00071+125|title=Fatty Acid Synthesis}}</ref> [[glycerolipid]] metabolism,<ref>{{cite web|url=http://www.genome.jp/dbget-bin/show_pathway?hsa00561+125|title=Glycerolipid Metabolism}}</ref> and [[bile acid biosynthesis]] pathways.<ref>{{cite web|url=http://www.genome.jp/dbget-bin/show_pathway?hsa00120+125|title=Bile Acid Biosynthesis}}</ref> 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 structures===
-A basic organizing theme in biological systems is that increasing complexity in specialized [[Biological tissue|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]],<ref>{{cite journal |last1=Tanaka |first1=Furnika |last2=Shiratori |first2=Yasushi |last3=Yokosuka |first3=Osarnu |last4=Imazeki |first4=Furnio |last5=Tsukada |first5=Yoshio |last6=Omata |first6=Masao |title=Polymorphism of Alcohol-Metabolizing Genes Affects Drinking Behavior and Alcoholic Liver Disease in Japanese Men |journal=Alcoholism: Clinical and Experimental Research |date=June 1997 |volume=21 |issue=4 |pages=596–601 |doi=10.1111/j.1530-0277.1997.tb03808.x |pmid=9194910 }}</ref> which is the primary site for alcohol catabolism. Variations in genes influence alcohol metabolism and drinking behavior.<ref>{{cite journal | pmid = 11762132 | volume=49 | issue=9 | title=Genetic polymorphisms of alcohol metabolizing enzymes. | date=Nov 2001 | journal=Pathol Biol (Paris) | pages=703–9 | doi=10.1016/s0369-8114(01)00242-5| last1=Agarwal | first1=D.P }}</ref>
-==Thermodynamic considerations==
-===Energy thermodynamics===
-====Energy calculations====
-The reaction from ethanol to [[carbon dioxide]] and [[water]] is a complex one that proceeds in at least 11 steps in humans. Below, the [[Gibbs free energy]] of formation for each step is shown with ΔG<sub>f</sub> values given in the CRC.<ref>CRC Handbook of Chemistry and Physics, 81st Edition, 2000</ref>
-Complete reaction:<br />
-C<sub>2</sub>H<sub>6</sub>O(ethanol) → C<sub>2</sub>H<sub>4</sub>O(acetaldehyde) → C<sub>2</sub>H<sub>4</sub>O<sub>2</sub>(acetic acid) → acetyl-CoA → 3H<sub>2</sub>O + 2CO<sub>2</sub>.<br />
-ΔG<sub>f</sub> = Σ ΔG<sub>fp</sub> − ΔG<sub>fo</sub>
-=====Step one=====
-C<sub>2</sub>H<sub>6</sub>O(ethanol) + [[NADH|NAD]]<sup>+</sup> → C<sub>2</sub>H<sub>4</sub>O(acetaldehyde) + [[NADH]] + H<sup>+</sup><br />
-Ethanol: {{val|−174.8|u=kJ/mol}}<br />
-[[Acetaldehyde]]: {{val|−127.6|u=kJ/mol}}<br />
-ΔG<sub>f1</sub> = {{val|−127.6|u=kJ/mol}} + {{val|174.8|u=kJ/mol}} = {{val|47.2|u=kJ/mol}} (endergonic)<br />
-ΣΔG<sub>f</sub> = {{val|47.2|u=kJ/mol}} (endergonic, but this does not take into consideration the simultaneous reduction of NAD<sup>+</sup>.)
-=====Step two=====
-C<sub>2</sub>H<sub>4</sub>O(acetaldehyde) + [[NADH|NAD]]<sup>+</sup> + H<sub>2</sub>O → C<sub>2</sub>H<sub>4</sub>O<sub>2</sub>(acetic acid) + [[NADH]] + H<sup>+</sup><br />
-Acetaldehyde: {{val|−127.6|u=kJ/mol}}<br />
-[[Acetic acid]]: {{val|−389.9|u=kJ/mol}}<br />
-ΔG<sub>f2</sub> = {{val|−389.9|u=kJ/mol}} + {{val|127.6|u=kJ/mol}} = {{val|−262.3|u=kJ/mol}} (exergonic)<br />
-ΣΔG<sub>f</sub> = {{val|−262.3|u=kJ/mol}} + {{val|47.2|u=kJ/mol}} = {{val|−215.1|u=kJ/mol}} (exergonic, but again this does not take into consideration the reduction of [[NADH|NAD]]<sup>+</sup>.)
-=====Step three=====
-C<sub>2</sub>H<sub>4</sub>O<sub>2</sub>(acetic acid) + CoA + ATP → Acetyl-CoA + AMP + PP<sub>i</sub>
-ΔG<sub>f3</sub> = {{val|−46.8|u=kJ/mol}}<ref>{{Cite web|url=https://biocyc.org/META/NEW-IMAGE?type=REACTION&object=ACETATE--COA-LIGASE-RXN|title=MetaCyc EC 6.2.1.1}}</ref>
-=====Steps 4 through 11=====
-After this the acetyl-CoA enters the TCA cycle and is converted to 2 CO<sub>2</sub> 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:<br />
-Acetic acid: {{val|−389.9|u=kJ/mol}}<br />
-H<sub>2</sub>O + 2CO<sub>2</sub>: {{val|−1500.1|u=kJ/mol}}<br />
-ΔG<sub>f4</sub> = {{val|−1500|u=kJ/mol}} + {{val|389.6|u=kJ/mol}} = {{val|−1110.5|u=kJ/mol}} (exergonic)<br />
-ΣΔG<sub>f</sub> = {{val|−1110.5|u=kJ/mol}} − {{val|215.1|u=kJ/mol}} = {{val|−1325.6|u=kJ/mol}} (exergonic)
-====Discussion of calculations====
-If catabolism of alcohol goes all the way to completion, then we have a very exothermic event yielding some {{val|1325|u=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 {{val|215.1|u=kJ/mol}}. At the very least, the theoretical limits on energy yield are determined to be {{val|-215.1|u=kJ/mol}} to {{val|-1325.6|u=kJ/mol}}. It is also important to note that step 1 on this reaction is endothermic, requiring {{val|47.2|u=kJ/mol}} of alcohol, or about 3 molecules of [[adenosine triphosphate]] (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 [[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 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<sup>+</sup>, mainly via the hepatic enzyme [[alcohol dehydrogenase]] IB (class I), beta polypeptide (ADH1B, EC 1.1.1.1). The gene coding for this enzyme is located on chromosome 4, locus.<ref>https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NC_000004.10&from=100446552&to=100461581&strand=2&dopt=gb 4q21-q23</ref> 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, [[hydroxysteroid]]s, and [[lipid peroxide|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.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=125|title=ADH1B alcohol dehydrogenase 1B (class I), beta polypeptide [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2018-04-28}}</ref> 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).<ref name="auto">Ernst van Faassen and Onni Niemelä, Biochemistry of prenatal alcohol exposure, NOVA Science Publishers, New York 2011.{{page needed|date=January 2020}}</ref> 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.<ref>{{cite journal |last1=Nava-Ocampo |first1=Alejandro A. |last2=Velázquez-Armenta |first2=Yadira |last3=Brien |first3=James F. |last4=Koren |first4=Gideon |title=Elimination kinetics of ethanol in pregnant women |journal=Reproductive Toxicology |date=June 2004 |volume=18 |issue=4 |pages=613–617 |doi=10.1016/j.reprotox.2004.02.012 |pmid=15135856 }}</ref> CYP2E1 expression and activity have been detected in various human fetal tissues after the onset of organogenesis (ca 50 days of gestation).<ref>{{cite journal |last1=Brzezinski |first1=Monica R. |last2=Boutelet-Bochan |first2=Helene |last3=Person |first3=Richard E. |last4=Fantel |first4=Alan G. |last5=Juchau |first5=Mont R. |title=Catalytic Activity and Quantitation of Cytochrome P-450 2E1 in Prenatal Human Brain |journal=Journal of Pharmacology and Experimental Therapeutics |date=1 June 1999 |volume=289 |issue=3 |pages=1648–1653 |pmid=10336564 |url=http://jpet.aspetjournals.org/content/289/3/1648.long }}</ref> 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|Microsomal Ethanol Oxidizing System]] (MEOS)<ref>{{cite journal |last1=Lieber |first1=Charles S. |title=The Discovery of the Microsomal Ethanol Oxidizing System and Its Physiologic and Pathologic Role |journal=Drug Metabolism Reviews |date=25 October 2004 |volume=36 |issue=3–4 |pages=511–529 |doi=10.1081/dmr-200033441 |pmid=15554233 |s2cid=27992318 }}</ref> and its activity in fetal tissues is thought to contribute significantly to the toxicity of maternal ethanol consumption.<ref name="auto"/><ref>Pregnancy and Alcohol Consumption, ed. J.D. Hoffmann, NOVA Science Publishers, New York 2011.{{page needed|date=January 2020}}</ref> In presence of ethanol and oxygen, CYP2E1 is known{{by whom|date=January 2020}} to release superoxide radicals and induce the oxidation of polyunsaturated fatty acids to toxic aldehyde products like 4-hydroxynonenal (HNE).{{citation needed|date=January 2020}}
-===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]] 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.<ref>{{Cite web |url=https://ntp.niehs.nih.gov/ntp/roc/content/profiles/acetaldehyde.pdf |title=Acetaldehyde |access-date=2010-04-11 |archive-url=https://web.archive.org/web/20100605101724/http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s001acet.pdf |archive-date=2010-06-05 |url-status=live }}</ref> 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 1.2.1.3). In humans, the gene coding for this enzyme is found on chromosome 12, locus q24.2.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NC_000012.10&from=110688729&to=110732167&dopt=gb|title=Homo sapiens chromosome 12, reference assembly, complete sequence - Nucleotide - NCBI|website=www.ncbi.nlm.nih.gov|date=3 March 2008|access-date=2018-04-28}}</ref> There is variation in this gene leading to observable differences in catalytic efficiency between people.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=217|title=ALDH2 aldehyde dehydrogenase 2 family member [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2018-04-28}}</ref>
-===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).<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=55902|title=ACSS2 acyl-CoA synthetase short chain family member 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2018-04-28}}</ref> 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 [[citric acid cycle]].
-==See also==
-* [[Alcohol (drug)]]
-==References==
-{{Reflist}}
-==Further reading==
-* {{cite journal |last1=Carrigan |first1=Matthew A. |last2=Uryasev |first2=Oleg |last3=Frye |first3=Carole B. |last4=Eckman |first4=Blair L. |last5=Myers |first5=Candace R. |last6=Hurley |first6=Thomas D. |last7=Benner |first7=Steven A. |title=Hominids adapted to metabolize ethanol long before human-directed fermentation |journal=Proceedings of the National Academy of Sciences |date=13 January 2015 |volume=112 |issue=2 |pages=458–463 |doi=10.1073/pnas.1404167111 |pmid=25453080 |pmc=4299227 |bibcode=2015PNAS..112..458C |doi-access=free }}
-{{Metabolism}}
-[[Category:Ethanol]]
-[[Category:Metabolism]]