HOW DOES THE BODY DEAL WITH ALCOHOL AND DO WE ALL HAVE THE SAME TOLERANCE TO IT?
PREAMBLE
Unlike tobacco, which the human body cannot metabolize because its consumption is relatively recent, dating back from the beginning of the 16th century, the human body has been programmed to drink alcohol for 10 million years[i]. Until now, we thought that our ability to metabolize alcohol dated back to the Neolithic period, around ten thousand years ago, when humans first became sedentary. To carry out fermentation in quantities that can be consumed by a population, you need equipment that did not exist before this date. But, around 10 million years ago, the Earth cooled, food sources changed and some primates began to explore life on land. This new way of life meant that, for the first time, primates began to eat not only fruit picked from trees, but also fallen fruit, and fallen fruit, when exposed to bacteria in the environment converts sugar into alcohol and begins to accumulate ethanol. This led to a significant increase in the ADH4 enzyme (see below), which is one of the two alcohol detoxification enzymes.
THE METABOLISM OF ALCOHOL BY THE BODY
The body metabolizes alcohol in two ways
1. By oxidation of alcohol by two enzymes, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH).
Alcohol is converted to acetaldehyde by the enzyme alcohol dehydrogenase (ADH) which, in turn is converted to acetic acid by other enzymes, aldehyde dehydrogenases (ALDH).
Alcohol has low toxicity and acetic acid is non-toxic.
It is acetaldehyde, the intermediate product, which is potentially the toxic component of this process.
This substance is classified as potentially harmful to humans but is not yet classified as a carcinogen due to lack of conclusive evidence. Its classification is in group 2B[1] a possible carcinogenic substance.
In the human body, acetaldehyde is rapidly metabolized and is only found in small quantities when the subject is intoxicated (less than 1 µM)[ii]; it is completely absent when alcohol has been eliminated from the body[iii].
In 2023 a research team from the University of California Davis highlighted the substance responsible for the headaches of certain subjects following a small consumption of red wine. A flavanol called quercetin, found almost exclusively in red wine, is transformed in the body into various substances. One of them, quercetin 3-O-glucuronide, has been shown to be particularly effective in blocking the enzyme ALDH that converts acetaldehyde into acetic acid[iv].
2. Through the cytochrome P 4502E1 (CYP2E1)[2]
Cytochrome P 4502E1 (CYP2E1) is the second most important pathway in alcohol metabolism. The cytochrome converts alcohol to acetaldehyde which is then converted to acetic acid by the enzymes acetaldehyde dehydrogenase (ALDH). However, the free radicals[3] generated during the absorption of alcohol do not seem to be responsible for oxidative stress and the overall aggression caused since the activity of cytochrome and other markers of oxidative stress are not correlated in subjects with excessive and chronic alcohol consumption[v] [vi] [vii] [viii] .
It also appears that only 10% of alcohol metabolism is carried out by the cytochrome pathway[ix].
In cases of moderate alcohol consumption, there is no accumulation of acetaldehyde and no activation of the cytochrome CYP2E1, therefore no production of free radicals which could cause the induction of cancers.
NB: However, chronic excessive alcohol consumption with the presence of an accumulation of acetaldehyde, however small it may be, and activation of cytochrome CYP2E1 are very likely causes of increased cancer risk.
We can logically conclude that there is a “threshold” of alcohol consumption beyond which risks are taken by the consumer. We will try to establish this safety limit (minimum risk) in a future article.
ALCOHOL TOLERANCE: ARE WE ALL EQUAL?
We observe great variability in the capacity of the two enzymes that metabolize alcohol between men and women, young and old, and between different populations around the world. Women do not have the same ability as men to metabolize alcohol because the genetic expression of their alcohol dehydrogenase is lower than in men. Historically, women have drunk less alcohol than men and therefore have acquired less resistance[x].
There are seven different types of alcohol dehydrogenases (ADH1 to ADH7). Likewise, there are several variations of the enzyme acetaldehyde dehydrogenase, both enzymes also exhibit genetic polymorphism[4].
It is the polymorphism on the ADLH2 enzyme that is most important. ADLH2*1 is present in all Caucasians and is a very active enzyme, while ADLH2*2, present in 50% of Asians, is largely inactive.
Subjects deficient in ADLH2*1 present an accumulation of acetaldehyde during alcohol consumption which results in an accumulation of blood in the face (redness effect) and signs of intolerance to alcohol (headaches, hypotension, tachycardia and heartburn). This gives them either an advantage against alcoholism, as the negative effects act as a deterrent to alcohol consumption, or an increased risk of esophageal cancer if they persist in drinking alcohol[xi] [xii] [xiii]. Research found that 41% of Japanese people who did not consume alcohol had ADHL2 deficiency, while only 2% were in the alcohol drinking group. Similarly in Taiwan, 30% of subjects were deficient in ALDH2 in the group not consuming alcohol while there were only 6% in the group consuming alcohol[xiv] [xv]. It is cultural differences that explain the phenomenon. Water quality deteriorated in the Middle Ages as cities expanded. In order to make water drinkable, the Caucasians used the aseptic fermentation technique because they had vineyards and cereals while the Asians boiled the water because they grew tea. We can therefore conclude that the process of neutralizing alcohol within the body varies within the world population but that within well-identified groups it can be relatively homogeneous.
[1] https://www.cancer-environnement.fr/fiches/expositions-environnementales/acetaldehyde/#:~:text=L%27acétaldéhyde%20est%20un%20liquide,retrouvé%20naturellement%20dans%20l%27environnement.
[2] Family of enzymes, comprising a large number of members, which are responsible for the oxidative metabolism of very diverse molecules of endogenous origin (steroid hormones, fatty acids, vitamins, etc.) or exogenous (drugs, pollutants, toxicants, and various agents.
[3] Everything that generates attacks at the cell level to make us age or even make us sick is due to free radicals. They are produced during certain familiar situations: breathing, smoking, infections, inflammation, stress, sun exposure, exposure to pollutants, excessive food intake.
[4] Different variants of enzymes, which are very common in nature. It reflects the adaptability of human beings to different environments. The different blood groups in humans are undoubtedly the best example to understand what generic polymorphism is.
[i] Hominids adapted to metabolize ethanol long before human-directed fermentation. December 1, 2014Matthew A. Carrigan, Oleg Uryasev, Carole B. Frye, et Steven A.
[ii] Enzymes du végétal de l’alcool disc.vjf.inserm.fr/basisrapports/alcool_effets/alcool_effets_ch2.pdf
[iii] Eckström et Ingelman-Sundlerg. Rat liver microsomal NADPH supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P450 (P450 IIE1).Biochem Pharmacol 1989.38:1313-1319.
[iv] Inhibition of ALDH2 by quercetin glucuronide suggests a new hypothesis to explain red wine headaches. Apramita Devi, Morris Levin et Andrew L. Waterhouse, https://www.nature.com/articles/s41598-023-46203-y
[v] BORRAS E, COUTELLE C, ROSELL A, FERNANDEZ-MUIXI F, BROCH M et al. Genetic polymorphism of alcohol dehydrogenase in Europeans: the ADH2*2 allele decreases the risk for alcoholism and is associated with ADH3* 1. Hepatology 2000, 31: 984-989
[vi]Thomasson HR, Edenberg HJ, Crabb DW, et al. (April 1991). « Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men ». American Journal of Human Genetics 48 (4): 677–81. PMID 2014795.
[vii] Crabb DW, Matsumoto M, Chang D, You M (February 2004). « Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology ». The Proceedings of the Nutrition Society 63 (1): 49–63. doi:10.1079/PNS2003327. PMID 15099407.
[viii] Roberts C, Robinson SP. Alcohol concentration and carbonation of drinks: the effect on blood alcohol levels. J Forensic Leg Med. 2007 Oct; 14(7):398-405. Epub 2007 May 16.
[ix] Frezza, M.; Di Padova, C.; Pozzato, G.; Terpin, M.; Baroana, E.; & Lieber. C.S. High blood alcohol levels in women: The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. The New England Journal of Medicine 322(2):95-99, 1990
[x] BORRAS E, COUTELLE C, ROSELL A, FERNANDEZ-MUIXI F, BROCH M et al. Genetic polymorphism of alcohol dehydrogenase in Europeans: the ADH2*2 allele decreases the risk for alcoholism and is associated with ADH3* 1. Hepatology 2000, 31: 984-989
[xi] Roberts C, Robinson SP. Alcohol concentration and carbonation of drinks: the effect on blood alcohol levels. J Forensic Leg Med. 2007 Oct; 14(7):398-405. Epub 2007 May 16.
[xii] Crabb DW, Matsumoto M, Chang D, You M (February 2004). « Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology ». The Proceedings of the Nutrition Society 63 (1): 49–63. doi:10.1079/PNS2003327. PMID 15099407.
[xiii] Roberts C, Robinson SP. Alcohol concentration and carbonation of drinks: the effect on blood alcohol levels. J Forensic Leg Med. 2007 Oct; 14(7):398-405. Epub 2007 May 16.
[xiv] Genetic Influences Affecting Alcohol Use Among Asians. Tamara L. Wall, Ph.D. and Cindy L.Ehlers, Ph.D. Alcohol Health Res World. 1995; 19(3): 184–189.
[xv] Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes’ toxicity. Che-Hong Chen, Julius C.B. Ferreira, Amit U. Joshi Matthew C. Stevens , Sin-Jin Li , Jade H.-M. Hsu , Rory Maclean , Nicholas D. Ferreira , Pilar R. Cervantes , Diana D. Martinez , Fernando L. Barrientos , Gibran H.R. Farmers and Daria Mochly-Rosen. eBioMedicine-Lancet. Volume 55, May 2020, 102753