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mercredi, 12 septembre 2012




Claude Gilois


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Human beings and indeed animal species genetically possess the ability to neutralize alcohol produced during the digestion and the absorption of alcoholic substance found in nature. However, alcohol production during digestion is minimal compared to cultural consumption that stems back from the settlement of mankind from a population of pickers/hunters to a population of farmers some 10,000 years ago.  In terms of the history of mankind it is long and short at the same time and, as we will see, the ability to metabolise alcohol varies considerably among the world’s population. The ability to detoxify alcohol is therefore largely an acquired phenomenon and a phenomenon that is still in constant evolution.


There are three pathways by which alcohol can be metabolised by the human body.   We will describe two here as the third one is minor compared to the other two.


  1. By the oxidation of alcohol through two enzymes, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH).

To keep it simple, alcohol is converted to acetyldehyde by the alcohol dehydrogenase enzyme (ADH) which, in turn, is converted to acetic acid by another enzyme acetyldehydrogense (ALDH).

Alcohol has a weak toxicity and the acetic acid is non-toxic. It is the acetaldehyde which is potentially the toxic component in this process. This substance is classified as potentially harmful for man but is not yet classified as a cancerous substance due to lack of conclusive proof (1). In the human body the acetaldehyde is quickly metabolised by the body and it can only be found in a small quantity when the subject is intoxicated (less than 1 µM) (i). It is totally absent when the alcohol has been eliminated from the body (ii) . 

  1.  Through the cytochrome P 4502E1 (CYP2E1)

The cytochrome (2) P 4502E1 (CYP2E1) is the second most important pathway for the metabolism of alcohol.  The cytochrome converts the alcohol to acetylaldehyde which is then converted to acetic acid by the enzyme acetyldehydrogense (ALDH).   However, the free radicals generated during the absorption of alcohol do not appear to be responsible for the oxidative stress as the activity of the cytochrome and the other oxidative stress markers are not correlated in subjects who are excessive chronic consumers of alcohol (iii), (iv), (v) (vi).

It also appears that only 10% of the metabolism of alcohol is achieved through the cytochrome pathway (vii).

In case of a moderate consumption of alcohol, there is no build-up of acetaldehyde and no activation of the cytochrome CYP2E1, therefore no  production of free radicals that may cause induction of cancer

However,  a chronic excessive consumption of alcohol with the presence of acetaldehayde build-up, no matter how small, and the activation of the cytochrome CYP2E1 are highly probable causes of increased risk of cancer.

We can logically conclude that there is a ‘cut off point’ of consumption of alcohol beyond which risks are being taken by the consumer. We will attempt to establish this safe limit (minimum risk) in our next article.  


We observe a great deal of variability in the ability of the two enzymes that metabolise alcohol between men and women, young and old and between different populations of the world. Women do not have the same capacity as men in metabolising alcohol  as the genetic expression of their alcohol dehydrogenase is weaker than in men (viii).  

There are seven different types of alcohol dehydrogenases (ADH1 to ADH7). Similarly there are several variants of the enzyme acetaldehyde dehydrogenase. Both enzymes also exhibit genetic polymorphism (3).

It is the polymorphism on the enzyme ADLH2 that has the most importance.  ADLH2*1 is present in all Caucasians and it is a very active enzyme,  while the ADLH2*2 which is present in 50% of Asians is largely inactive.

The subjects who are deficient in ADLH2*1 have a build-up of acetaldehyde during the consumption of alcohol which expresses itself by an accumulation of blood in the face (flushed effect) and signs of alcohol intolerance  (headaches, hypotension, tachycardia and gastric burning).  This provides them with either an advantage against alcoholism as the negative effects act as a deterrent against the consumption of alcohol or alternatively an increased risk of oesophageal cancers if they persist with the consumption (ix), (x) (xi).  A research has found that 41% of Japanese who did not consume any alcohol were deficient in ADHL2 while only 2% were in the group that consumed alcohol. Similarly in Taiwan, there were 30% of subjects who were deficient in ALDH2 in the group that did not consume alcohol while there were only 6% in the group that did consume alcohol (xii).



It is the cultural differences that explain the phenomenon. The quality of the water deteriorated in the middle ages, as towns grew bigger. In order to make the water drinkable, the Caucasians used the aseptic technique of fermentation because they had vines and grains while the Asians resorted to boiling the water because they grew tea.    We can therefore conclude that the process of neutralising alcohol within the body varies quite a lot in the world population but that within well-identified groups it can be relatively homogenous. 

(1) Directive 2001/59/CE from the EU Commission of 6th August 2001

(2) They enhance reactions within the cellular respiratory chain..


(3) Different variants of the enzymes and this is very common in nature. It reflect the adaptability of the human being to different environments..

(i) Enzymes  du métabolisme de l’alcool disc.vjf.inserm.fr/basisrapports/alcool_effets/alcool_effets_ch2.pdf


(i) Swift R.  Alcohol hangover.  Mechanisms and mediators.  Alcohol Health Res World. 1998;22:54-60.


(iii) Eckström et  Ingelman-Sundlerg .Rat liver microsomal NADPH supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P450 (P450 IIE1).Biochem Phamacol 1989.38:1313-1319.


(iv) Dupond I, Bodenez P, Berthou F, Simon B, Bardou LG, Lucas D. Cytochrome P4502E1 activity and oxidative stress in alcoholic patients. Alcohol 2000, 25:98-103.

(v) ROBERTS BJ, SHOAF SE, JEONG KS, SONG BJ. Induction of CYP2E1 in liver, kidney, brain and intestine during chronic ethanol administration and withdrawal. Biochem Biophys Res Commun 1994, 205: 1064-107 1


(vi) MISHIN VM, ROSMAN AS, BASU P, KESSOVA I, ONETA CM, LIEBERS CS. Chlorzoxazone pharmacokinetics as a marker of hepatic cytochrome P4502E1 in humans. Am J Gastroenterol 1998, 93: 2154-2161


(vii) LUCAS D, MENEZ C, GIRRE C, BODENEZ P, HISPARD E, MENEZ JF. Decrease in cytochrome P4502E1 as assessed by the rate of chlorzoxazone hydroxylation in alcoholics during the withdrawal phase. Alcohol Clin Exp Res 1995a, 19: 362-366


(viii) 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


(ix) 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


(x) 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.


(xi) 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.


(xii) 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.


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