BIOCHEMICAL AND NUTRITIONAL ASPECTS OF ALCOHOLISM.
Normal metabolism of ethanol involves oxidation to acetic
acid, conversion to acetyl CoA and processing in the usual
mitochondrial respiration. Alcohol is thus a source of energy; the
number usually given for caloric value is about 7 kcalories/g. Normal
ethanol intake varies greatly -- averaged over the US population it
is about 5 % of energy intake -- and a small amount is supplied by
the action of intestinal bacteria. This normal metabolism assumes a
relatively balanced diet and moderate levels of alcohol (less than 10
- 20 % of caloric intake).
The major reactions are:
1. Alcohol dehydrogenase: ethanol + NAD+ ----> acetaldehyde +
NADH
2. Aldehyde dehydrogenase: acetaldehyde + NAD+ ----> acetic
acid + NADH
Click here to review general points
on oxidative metabolism and NAD.
High levels of alcohol may not allow the mitochondrial
processing of NADH to keep up. This, especially in association with
low food intake, can lead to a number of metabolic consequences.
Build-up of intermediates. Acetaldehyde from the alcohol
dehydrogenase reaction is extremely toxic and may cause several kinds
of damage. Aldehydes are generally reactive with amino groups and may
interact with proteins. Acetaldehyde also competes for the plasma
carrier of pyridoxal (vitamin B6). This can exacerbate what may
already be a dietary deficiencies in vitamins.
The aldehyde dehydrogenase reaction leads to production
of acetic acid. There is a limited ability to convert this to
acetyl CoA and acetic acid can appear in the blood leading to
acidosis. (Recall from Biochemistry that the reason ketone bodies
have evolved is that they are a method for the liver to supply
substrates to other tissues with a lower ratio of acid/carbon than
acetic acid).
Deficiency in NAD+. Because the two oxidative reactions
above require, NAD+, this form of the coenzyme can become limiting
and NADH can build up. This can cause the following problems:
In order to regenerate NAD+ there will be increased anerobic
metabolism, that is, conversion of pyruvate to lactate by lactate
dehydrogenase. This can lead to lactic acidosis.
pyruvate + NADH ----> lactate + NAD+
This demand for pyruvate can reduce its availability for
gluconeogenesis (pyruvate -> oxaloacetate -> PEP). In
combination with low food intake this can lead to
hypoglycemia. The TCA cycle, via the malate dehydrogenase
reaction is potentially another source of oxaloacetate:
malate + NAD+ ---> oxaloacetate + NADH
You may remember, however, that thermodynamically the malate
dehydrogenase reaction favors malate and, as noted above, you already
have an excess of NADH which will push the reaction away from
oxaloacetate and further repress gluconeogenesis.
The microsomal ethanol oxidizing
system. At a certain level of alcohol -- estimates are at 10 % of
caloric intake -- a second oxidizing system becomes important. There
is a P450 (or microsomal) oxidizing system that is inducible and will
become important as the levels of alcohol become higher. One might
think of this as the point at which the body is dealing with alcohol
as a toxic agent rather than a dietary source. The components of this
system are inducible and account for the increased tolerance of
alcohol in heavy drinkers. The caloric output in terms of NADH is
less than for the normal alcohol dehydrogenase system but, more
important, the system will add to the load of acetaldehyde and
acetate and interfere with the normal functioning of the P450 system.
This is one of the sources of problems associated with alcohol
consumption while on medication since many drugs are processed
through the microsomal P450 system.
Click here to see Background on the
microsomal oxidizing system.
Vitamin deficiencies in
alcoholism. Alcoholics develop nutritional deficiencies both
because alcohol abuse is frequently associated with poor diet and
because of the effect of ingested alcohol on either absorption or
processing of nutrients. Two of the most important are B6, niacin,
thiamin and folate. Alcoholism is probably the most common condition
in which thiamin and folate deficiencies are seen and, in its extreme
form, causes the neurologic disorders known collectively as the
Wernicke-Korsakoff syndrome.
Click
here for a case Study of Vitamin-deficient Alcoholic
Effects on liver lipid metabolism. The demands on NAD+
described above also show up as an inability to metabolize fatty
acids in the liver; recall that b-oxidation also uses NAD+ as one of
the oxidizing agents. The results of this are fat accumulation in the
liver (fatty liver) and increased VLDL. From a clinical standpoint,
fatty liver and the accompanying enlargement of the liver can be
reversed if alcohol is withdrawn. However, continued damage to the
liver can result in alcoholic hepatitis with cell death and
inflammation and this is sometimes fatal. Some drinkers, after years
of abuse, can develop cirrhosis of the liver in which scar tissue is
formed. Cirrhosis occurs in about 25 % of heavy drinkers although it
can be caused by other factors.
Summary. The nutritional and biochemical consequences of
alcohol abuse are due to a combination of what occurs -- the
metabolism of ethanol -- and what doesn't occur -- normal intake of
food and vitamins. To be metabolized, the alcohol must be oxidized to
acetic acid (ultimately converted to acetyl CoA) and this requires
NAD+ which can become in a limiting metabolite. The NADH that builds
up will drive pyruvate to lactate which can lead to acidosis. The
pyruvate is now not available for gluconeogenesis and if, as is
common in serious alcoholism, the patient is not eating, hypoglycemia
can result. The high NADH/NAD+ ratio will affect other processes such
as b-oxidation. One clinical manifestation is liver disorders
associated with alcoholism: fatty liver, alcoholic hepatitis and,
sometimes, cirrhosis. The burden on oxidizing systems also leads to
increased use of the P450 or microsomal oxidizing system which can
have important effects on steroid metabolism and other processes
involving this system. Finally, alcoholism is frequently associated
with gross malnutrition which is often seen clinically in vitamin
deficiencies.
Questions for Discussion.
1.NAD+/NADH is a very important coenzyme system in biochemistry.
How would you describe its general role and what part does it play in
the consequences of alcoholism ?
2.Describe the function of P450 oxidizing system and its role in
nutritional and biochemical aspects of alcoholism.
3.Discuss the role of alcoholism in liver disease.
4.Looking at the big picture of nutrition. if you took vitamin
pills, why could you not take all of your calories from alcohol ?
(Aside from the intoxication).
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