Author: Rich Van Konynenburg, Ph.D.
Ethanol is metabolized primarily in the liver, and primarily by the pathway that involves the enzymes alcohol dehydrogenase and aldehyde dehydrogenase. Both these enzymes use NAD+ as a cofactor, chemically reducing it to NADH. Ordinarily, NADH is utilized by the respiratory chain to produce ATP. However, when alcohol is being metabolized, the production rate of NADH can be so high that the respiratory chain cannot keep up. When this occurs, the ratio of NADH to NAD+ rises above its usual low value. Since the Krebs cycle depends for its operation on a low value of this ratio, this rise inhibits the operation of the Krebs cycle in the liver cells. The result of this is that the liver cells are not able to carry on gluconeogenesis at their usual rates. Among other substrates, gluconeogenesis uses lactic and pyruvic acids, converting them back to glucose. All of this is well-accepted textbook biochemistry.
Now, I have suggested that the way this particularly impacts many PWCs is that their red, "slow-twitch" skeletal muscle cells are not able to carry on oxidative metabolism at normal rates, because the depletion of glutathione in these cells allows a rise in peroxynitrite (Note that Prof. Martin Pall has published extensively on peroxynitrite in CFS). This puts partial blockades in the Krebs cycle (at aconitase) and in the respiratory chain (at cytochrome oxidase). The result is that these cells are unable to completely metabolize carbohydrates to carbon dioxide and water, as they normally do. Instead, they produce elevated levels of lactic and pyruvic acids from glycolysis of carbohydrates.
A normal, healthy person's body also produces lactic and pyruvic acids, but the rates are much smaller, because the skeletal muscle cells are able to consume it.
The excess lactic and pyruvic acids, above what can be consumed, are normally processed by gluconeogenesis in the liver and are returned to the blood as glucose, which can again be used as fuel in glycolysis in various cells. This cycle is called the Cori cycle.
In PWCs with alcohol intolerance, what I've suggested is that because gluconeogenesis is inhibited by the mechanism described above, and because PWCs depend on the Cori cycle (and hence on gluconeogenesis) more than do normal, healthy people, because of the partial blockades described above, the result is that they develop a backlog of lactic and pyruvic acids as well as a depletion of blood glucose levels, and this results in the very unpleasant combination of hypoglycemia and acidosis. I have suggested that this combination is what produces the symptoms in alcohol intolerance in many PWCs.
There are PWCs who are still able to tolerate alcohol. I suggest that these people have a greater liver capacity for metabolizing alcohol. Although I would certainly not generalize the following to all PWCs who are able to tolerate alcohol, I have been told by a few PWCs in this category that they customarily consumed fairly large quantities of ethanol before they became ill. There is a second pathway for the metabolism of alcohol in the liver, which involved cytochrome P450 enzymes. Since these are inducible, I suggest that these people have higher concentrations of these enzymes in their liver cells as a result of having adapted to high consumption of ethanol before they became ill. They thus do not suppress gluconeogenesis to the degree that the ethanol-intolerant PWCs do.
Rich Van Konynenburg, Ph.D.
as posted to the Co-Cure list March 16, 2005
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Last Revision: March 16, 2005
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