Alcohol is metabolized through three main pathways: 1) cytosolic alcohol dehydrogenase and mitochondrial aldehyde dehydrogenase, 2) microsomal ethanol oxidizing system, and 3) non-enzymatic oxidation. Acetaldehyde produced during metabolism is toxic and can damage liver cells, potentially leading to alcoholic hepatitis or cirrhosis over time with heavy drinking. Genetic differences in alcohol and aldehyde metabolizing enzymes also influence toxicity. Moderate drinking may provide some benefits but heavy drinking overwhelms the liver's ability to metabolize alcohol safely.

1. ALCOHOL METABOLISM

2. PRESENTED BY: ABHISHEK ROUTRAY
MBBS

3. Consumtion of alcohol is injurious to health

4. Alcohol beverage is a drink which contains
substantial amount of psychoactive drug ethanol.

5. Alcohol beverages have been produced and consumed by humans
since the Neolithic era ,evidences indicating the preparation of the
alcoholic drinks dating as far back as 8000 BC

6. Different alcoholic beverages
Distilled alcohol
Alcohol conc.—40 to 50%
 Rum----produced from molasses
 Whisky---produced from cereals
 Brandy ----produced from
 Vodka------produced from potato
Undistilled alcohol
Alcohol conc.---5 to 11%
 Beer---produced from barley malt
 Wine----- from fruit juice

7. It is preferred as a typical part of diet in western
part of the world but is not recommended for the
people of tropical part.
“Alcohol can be a food,drug or a poison depending
on the dose.”
-walker-

8. Although moderate drinking has some health
benefits but its detorius effect on liver
overweighs its good effects.

9. PROCESS OF METABOLISM IN BRIEF:
 Three vital organs are related to the metabolism of alcohol
as:
1. liver
2. Intestine
3. stomatch
But after being metabolized it affects the entire body

10. REQUIREMENTS OF ALCOHOL METABOLISM
ENZYMES REQUIRED:
- alcohol dehydrogenase
- aldehyde dehydrogenase
- microsomal ethanol oxidizing system(MEOS) enzymes
as cytochrome P450 and mixed function oxidase
isoenzymes as CYP2E1
N.B.
 Action of alcohol dehydrogenase is faster than that of aldehyde dehydrogenase.
 In fact activity of aldehyde dehydrogenase enzyme is more in case of the people of the western
 Each enzyme ADH,ALDH and CYP2E1 exists as a family of isoenzymes

11. Alcohol dehydrogenase:
-exists as a family of isoenzymes varying specificity of as the
chain length of the alcohol.
-The ADHs that exhibit the highest specificity for ethanol are
members of the ADH1 family.
-ADH1 hormone chiefly present in the liver having low Km for
ethanol so liver is main site for the alcohol metabolism.
 Though ADH 4 and ADH 2 has minor contribution to the
alcohol metabolism probably leads to its toxic effects as
acetaldehyde generated here may lead to cancer related to
heavy drinking

12. GENES SUBUNITS TISSUE DISTRIBUTION PROPERTIES
ADH1A alpha Most abundant in liver and adrenal
glands. Much lower levels
in kidney, lung, colon, small
intestine, eye, ovary, blood
vessels. None in brain or heart.
Km of 0.02 to 5 mM
for ethanol.
Active only with
ethanol
ADH1B beta same here
ADH1C gamma same here
ADH2 Primarily liver, lower levels in GI
tract.
Km of 23 mM for
ethanol
ADH3 pie Ubiquitously expressed, but at
higher levels in liver. The only
isozyme present in germinal
cells.
Relatively inactive
toward
ethanol (Km 3400
mM).
Active mainly toward
long-chain alcohols
ADH4 delta Present in highest levels in upper
GI tract, gingiva and mouth,
esophagus, down to the
stomach. Not present in liver.
Km of 58 mM. It is the
most
active of medium-
chain

13. ACETALDEHYDE DEHYDROGENASE
-acetaldehyde dehydrogenase oxidises acetaldehyde to
acetate.
-more than 80% of acetaldehyde oxidation occurs in
mitochondrial dehydrogenase enzyme(ALDH2) high low Km for
acetaldehyde (0.2mM) highly specific.
-remainder aldehyde gets oxidized by the ALDH1
N.B. additional function of aldehyde dehydrogenase is to act on variety of
organic alcohol, toxins and pollutants

18. -more than 100 different CYP isoenzymes exist with in
10 gene families.
-the isoenzyme having highest activity towards
ethanol is CYP2E1
-it has much higher Km value for ethanol than ADH1
-so greater proportion of ethanol is metabolized
through CYP2E1 at high level of ethanol consumtion
than low level.

20. METABOLIC PATHWAY:

21. -At first ethanol gets oxidized to acetaldehyde
through cytosolic ADH hormone with reduction of
NAD to NADH
- further on acetaldehyde oxidized to acetate by
ALDH enzyme with generation of NADH.
-acetate is activated to acetyl co enzyme A in the liver
BY synthetase enzyme

22. -then it can either enter the TCA cycle or the fatty acid
synthesis pathway.
-However, most of the acetate that is generated enters
the blood and is activated to acetyl-CoA in skeletal
muscles as they have high conc. Mitochondrial matrix
synthetase enzyme (ACS-II)
N.B in the above pathway the 1st formed aldehyde is a toxic
product but so not is the finally formed acetate as it is a part of
our regular diet.

24. -MEOS is the another principal pathway of alcohol
metabolism oxidises ethanol to aldehyde.
-CYP2E1 is major cytochrome P450 in this regard.
-which uses NADPH as an additional electron donor
and O2 as an electron acceptor.
N.B. This route accounts for only 10% to20% of ethanol oxidation
in a moderate drinker.

25. Variation in pattern of metabolism:
-GENOTYPE:Polymorphic forms of ADHs and
ALDHs can greatly affect the rate of ethanol
oxidation and the accumulation of
acetaldehyde. CYP2E1 activity may vary as much
as 20-fold among individuals, partly because of
differences in the inducibility of different allelic
variants.
-

26. DRINKING HISTORY:The level of gastric ADH
decreases and CYP2E1 increases
with the progression from a naive, to a moderate,
and to a heavy and chronic
consumer of alcohol.

27. GENDER:Blood levels of ethanol after consuming a drink are
normally higher for women than for men, partly because of lower
levels of gastric ADH activity in women. After chronic
consumption of ethanol, gastric ADH decreases in both men and
women but the gender differences become even greater alcohol
is distributed in a 12% smaller water space because a woman’s
body composition consists of more fat and less water than
that of a man.

28. QUANTITY:Small amounts of ethanol are metabolized most
efficiently through low Km pathway comprising of ADH-1and
ALDH.The MEOS, which has a much higher Km for
ethanol,functions principally at high concentrations of ethanol. So
prolonged activation of the MEOS may increase the risk of
alcohol induced liver diseases due to release of more free
radicals and acetaldehyde.

29. ATP generated during alcohol metabolism varies
as the route of alcohol metabolism
Through cytosolic ADH and
mitochondrial ALDH
 1 cytosolic NADH+ 1 mt NADH=
5ATP
 Activation of acetate to acetyl-co-
enzyme A requires 2 ATP
 Oxidation Acetyl –co-A in TCA cycle
and ETS =10 ATP
 However net ATP gained is 13
Through CYP2E1 of
Endoplasmic reticulum
 1st step oxidation from alcohol to
aldehyde consumes I NADPH in the
form of 2.5 ATP.
 Activation of acetate to acetyl –co-
enzyme A requires 2 ATP.
 Oxidation of acetate in the TCA
generates 10 ATP
 So net generated 8 ATP

30. TOXIC EFFECTS OF ALCOHOL
METABOLISM

31. CHANGES IN FATTY ACD METABOLISM-lipolysis of adipose
tissue and release of free fatty acid occurs after alcohol
consumtion due to epinephrine
-.they again re-esterified with TG by combining with gly-3-
phosphate.
-TAG are incorporated to VLDL enter the blood resulting
alcohol induced hyperlipidemia.
-overall high NADH and NAD+ ratio inhibits the fatty acid
oxidation thus they gets accumulated in the liver.

32. KETO ACIDOSIS:
-fatty acid acetyl co-A ketone bodies.
-high NADH/NAD+shifts the OAA in TCA cycle towards malate synthesis
so less OAA to synthesize citrate.
-thereby acetyl –co-a enters the ketone body synthesispathway instead
of the TCA cycle.
-so production of ketone bodies in the body remains in high conc but
use is prevented in tissue by acetate.
-therefore the ketoacidosis condition arises.

33. LACTIC ACIDOSIS:
-very high NADH/NAD+ conc. In the blood balance in the
lactate dehydrogenase reaction shifts the product towards
lactate production.
-elevation of blood lactate decrease the excretion of uric acid
resulting GOUT.
- so already GOUT patients are strictly advised not to consume
alcohol.

34. HYPOGLYCEMIA:
-alanine and lactate are major gluconeotic precursors.
-high NADH and NAD+ shifts lactate dehydrogenase
equllibbrium to lactate so pyruvate formed from alanine
converted to lactate again don’t enter the pathway.
-in normal glycolysis condition the above ration stops the
pathway at glyceroaldehyde 3 phosphate dehydrogenase stage.
-so from every point of view it prevents the utilization of glucose
thus hypoglycemic condition arises.

35. TOXICITY OF ACETALDEHYDE TO THE BODY:
-as we all know acetaldehyde is toxic to the body.
-if the acetaldehyde converts acetate so no accumulation no
toxicity.
-but if intake of alcohol is more the acetaldehyde takes time to
get oxidized and gets accumulated produces the toxic effect.
-aldehyde is highly reactive binds covalently to amino
groups, sulfhydryl groups, nucleotides, and phospholipids to form
“adducts.”

36. DISEASES:
1.alcohol induced hepatitis
2.hepatic cirrhocis

37. ALCOHOL INDUCED HEPATTIS:
-acetaldehyde-adduct formation with amino acids is a
general decrease in hepatic protein synthesis like
Calmodulin, ribonuclease,and tubulin.
-As a consequence of forming acetaldehyde adducts
of tubulin, there is a diminished
secretion of serum proteins and VLDL from the liver
-

38. -The liver synthesizes many blood proteins, including serum
albumin, blood coagulation factors, and transport proteins for
vitamins, steroids, and iron.
-These proteins accumulate in the liver together with lipid.
-The accumulation of proteins results in an influx of water within
the hepatocytes and a swelling of the liver that contributes to
portal hypertension and a disruption of hepatic architecture

39. Liver cirrohosis:
-irreversible injury to the liver
-enlarged full of fat, cross with collagen fibres.
-biosynthetic ,detoxification pathway synthesis of blood
proteins decreased.
-no urea cycle so ammonia gets accumulated in the liver.
-billirubins can not be excreted out gets deposited in many
tissues causing jaundice.

40. CIRROHTIC LIVER

42. COMPLICATIONS
 Jaundice ,yellow discoloration of the skin and
whites of the eyes
 Gallstones
 Bruising and bleeding easily
 Edema and ascites
 Hepatic encephalopathy (build up of toxins in
the brain causes both mental and physical
complication

44. CIRROHOTIC PATIENTS:

45. DIAGNOSIS:
 Symptoms
 Blood test
 Medical history
 Physical examination
 A liver biopsy (small piece of liver tissue is removed and studied in the lab)

50. TREATMENT:
 It depends upon the cause
and level of liver damage.
 Medication and life style can
be opted as treatment.
 Main goal of this treatment is
to prevent the further damage
to the liver cells
 When cirrhosis can not be
treated liver will not be able to
work liver transplant may be
required

51. How ever moderate amount of drinking is
good for health

53. But unfortunately moderate amount can
not be taken by the drinkers.