In the normal course of events acetyl coenzyme A, derived either from
pyruvate or the beta oxidation of fatty acids acids, and oxygen replenish
by oxidative phosphorylation any ATP that might have been used (1). For
this to occur NADH is needed, the rate of the reactions being determined
by Michaelis-Menten kinetics and the law of mass action.
As Paton has shown in his illustration (2) NAD is converted to NADH
by imbibing thereby decreasing [NAD+] and NAD+/NADH ratio. Conventional
thinking holds that the rise in [NADH] should be a mass action stimulus
for ATP resynthesis and accompanying need for acetyl coenzyme A, some of
which would be derived from the acetate being produced by the oxidation of
acetaldehyde by the aldehyde dehydrogenases. Unless the additional ATP is
used it will accumulate and inhibit glycolysis by mass action, a rise in
[ATP]/[AMP] ratio inhibiting phosphofructokinase, and/or the reduction in
[NAD+] inhibiting the glyceraldehyde-3-phosphate dehydrogenase reaction.
Should the utilisation of pyruvate be impaired lactate will rise and
because it is excreted in preference to uric acid, uric acid may also rise
and in so doing limit by mass action the rate at which adenine nucleotide
pool is being depleted.
Paton also shows that imbibing has the opposite effect upon [NADP+],
[NADPH] and [NADP+]/NADPH] ratio and in so doing inhibits the reductive
biosynthesis of fatty acids, and hence triglycerides, and no doubt steroid
hormones and nucleic acids. Not only should this cause an accumulation of
H+, as he shows, but also inhibit ATP-dependent enzyme activity in
accordance with the Daniel Atkinson energy charge hypothesis (3). This
effect can be expected to cause dysfunction but to be cytoprotetive unless
vital cellular functions are also compromised and apoptosis or necrosis
occurs.
"When the integrity of the gastric mucosa is destroyed, there is a
large passive diffusion of interstitial HCO3- from the nutrient side to
the luminal side of the tissue in vitro. In the absence of nutrient HCO3-
, rapid repair of superficial mucosal injuries is slowed markedly down or
does not take place at all. The effects of a high degree of luminal
acidification, which prevents rapid repair, can be counteracted by high
concentrations of nutrient HCO3-"(4). The reduction in bicarbonate
concentration might have compromised the ability to maintain a higher pH
and in so doing compromised repiar by inhibiting ATP-dependent enzyme
activity in accordance with the Daniel Atkinson hypothesis. Indeed when,
"Exclusion of the fluorescent dye propidium iodide was used to estimate
cell survival in rabbit gastric glands incubated in buffers of pHo 8.0-
2.0..mean survival (+/- SE) ..at 2 h in a HEPES buffer of 300 mosM at pHo
8.0, 7.0, 6.0, 4.0, and 2.0 was 80 +/- 3, 91 +/- 2, 90 +/- 2, 71 +/- 2,
and 17 +/- 4%, respectively"(5).
It has been known for many years that pharmacological concentrations
of luminal acid and alcohol can damage the gastric mucosa (6). It
certainly looks as though the damage the product of an energy deficit as
Menguy and Masters first suggested some 25 years ago (7). As in the heart
and possibly in glial cells betablockers may be cytoprotective possibly
because they limit the degree of uncoupling present. But cytoprotective is
accompanied by dysfunction and in the brain that can be undesirable.
The entire spectrum of the pathological effects seen with alcohol
abuse can be explained solely by different degrees an energy supply/demand
mismatch. These include, sedation, anaesthetia, sense of well being,
relaxation, disinhibition, and euphoria, intoxication, garrulousness,
elation, aggressiion, drowsiness, slurred speech, unsteadiness, loss of
consciousness, ventricular fibrillation, respiratory failure, inhalation
of vomit and, in those that recover, insomnia, nocturia, tiredness,
nausea, and headache.
In its earlier stages, however, the energy supply demand balance
could well be positive rather than negative. These are the effects most
imbibers may experience given the pleasure and beneficial effects of
imbibing in moderation.
1. Internal regulation of ATP turnover, glycolysis and oxidative
...www.ejbiochem.org/cgi/content/full/266/3/737
2. Alex Paton
Alcohol in the body
BMJ 2005; 330: 85-87
3. Fiddian-Green RG. eLetters re: David Roy Dantzker
Monitoring Tissue Oxygenation : The Quest Continues
Chest 2001; 120: 701-702
4. Silen W. Leakage of HCO3- and mucosal restitution.
J Intern Med Suppl. 1990;732:59-62.
5. Carter KJ, Lee HH, Goddard PJ, Yanaka A, Paimela H, Silen W Cell
survival in rabbit gastric glands: effect of extracellular pH, osmolarity,
and anoxia.
Am J Physiol. 1993 Aug;265(2 Pt 1):G379-87.
7. Menguy R, Masters YF. Mechanism of stress ulcer. Influence of
alpha-adrenergic blockade on stress ulceration and gastric mucosal energy
metabolism.
Am J Dig Dis. 1978 Jun;23(6):493-7.
Competing interests:
None declared
Competing interests:
No competing interests
10 January 2005
Richard G Fiddian-Green
FRCS, FACS
c/o Hrhold, Maitland and Co, 44 D. Londonover Street,
Rapid Response:
The benefical effects of alcohol.
In the normal course of events acetyl coenzyme A, derived either from pyruvate or the beta oxidation of fatty acids acids, and oxygen replenish by oxidative phosphorylation any ATP that might have been used (1). For this to occur NADH is needed, the rate of the reactions being determined by Michaelis-Menten kinetics and the law of mass action.
As Paton has shown in his illustration (2) NAD is converted to NADH by imbibing thereby decreasing [NAD+] and NAD+/NADH ratio. Conventional thinking holds that the rise in [NADH] should be a mass action stimulus for ATP resynthesis and accompanying need for acetyl coenzyme A, some of which would be derived from the acetate being produced by the oxidation of acetaldehyde by the aldehyde dehydrogenases. Unless the additional ATP is used it will accumulate and inhibit glycolysis by mass action, a rise in [ATP]/[AMP] ratio inhibiting phosphofructokinase, and/or the reduction in [NAD+] inhibiting the glyceraldehyde-3-phosphate dehydrogenase reaction. Should the utilisation of pyruvate be impaired lactate will rise and because it is excreted in preference to uric acid, uric acid may also rise and in so doing limit by mass action the rate at which adenine nucleotide pool is being depleted.
Paton also shows that imbibing has the opposite effect upon [NADP+], [NADPH] and [NADP+]/NADPH] ratio and in so doing inhibits the reductive biosynthesis of fatty acids, and hence triglycerides, and no doubt steroid hormones and nucleic acids. Not only should this cause an accumulation of H+, as he shows, but also inhibit ATP-dependent enzyme activity in accordance with the Daniel Atkinson energy charge hypothesis (3). This effect can be expected to cause dysfunction but to be cytoprotetive unless vital cellular functions are also compromised and apoptosis or necrosis occurs.
"When the integrity of the gastric mucosa is destroyed, there is a large passive diffusion of interstitial HCO3- from the nutrient side to the luminal side of the tissue in vitro. In the absence of nutrient HCO3- , rapid repair of superficial mucosal injuries is slowed markedly down or does not take place at all. The effects of a high degree of luminal acidification, which prevents rapid repair, can be counteracted by high concentrations of nutrient HCO3-"(4). The reduction in bicarbonate concentration might have compromised the ability to maintain a higher pH and in so doing compromised repiar by inhibiting ATP-dependent enzyme activity in accordance with the Daniel Atkinson hypothesis. Indeed when, "Exclusion of the fluorescent dye propidium iodide was used to estimate cell survival in rabbit gastric glands incubated in buffers of pHo 8.0- 2.0..mean survival (+/- SE) ..at 2 h in a HEPES buffer of 300 mosM at pHo 8.0, 7.0, 6.0, 4.0, and 2.0 was 80 +/- 3, 91 +/- 2, 90 +/- 2, 71 +/- 2, and 17 +/- 4%, respectively"(5).
It has been known for many years that pharmacological concentrations of luminal acid and alcohol can damage the gastric mucosa (6). It certainly looks as though the damage the product of an energy deficit as Menguy and Masters first suggested some 25 years ago (7). As in the heart and possibly in glial cells betablockers may be cytoprotective possibly because they limit the degree of uncoupling present. But cytoprotective is accompanied by dysfunction and in the brain that can be undesirable.
The entire spectrum of the pathological effects seen with alcohol abuse can be explained solely by different degrees an energy supply/demand mismatch. These include, sedation, anaesthetia, sense of well being, relaxation, disinhibition, and euphoria, intoxication, garrulousness, elation, aggressiion, drowsiness, slurred speech, unsteadiness, loss of consciousness, ventricular fibrillation, respiratory failure, inhalation of vomit and, in those that recover, insomnia, nocturia, tiredness, nausea, and headache.
In its earlier stages, however, the energy supply demand balance could well be positive rather than negative. These are the effects most imbibers may experience given the pleasure and beneficial effects of imbibing in moderation.
1. Internal regulation of ATP turnover, glycolysis and oxidative ...www.ejbiochem.org/cgi/content/full/266/3/737
2. Alex Paton Alcohol in the body BMJ 2005; 330: 85-87
3. Fiddian-Green RG. eLetters re: David Roy Dantzker Monitoring Tissue Oxygenation : The Quest Continues Chest 2001; 120: 701-702
4. Silen W. Leakage of HCO3- and mucosal restitution. J Intern Med Suppl. 1990;732:59-62.
5. Carter KJ, Lee HH, Goddard PJ, Yanaka A, Paimela H, Silen W Cell survival in rabbit gastric glands: effect of extracellular pH, osmolarity, and anoxia. Am J Physiol. 1993 Aug;265(2 Pt 1):G379-87.
6. Davenport HW. Ethanol damage to canine oxyntic glandular mucosa. Proc Soc Exp Biol Med. 1967 Dec;126(3):657-62.
7. Menguy R, Masters YF. Mechanism of stress ulcer. Influence of alpha-adrenergic blockade on stress ulceration and gastric mucosal energy metabolism. Am J Dig Dis. 1978 Jun;23(6):493-7.
Competing interests: None declared
Competing interests: No competing interests