ALCOHOL METABOLISM

PRESENTED BY: ABHISHEK ROUTRAY MBBS

Consumtion of alcohol is injurious to health

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

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

Different alcoholic beveragesDistilled alcoholAlcohol conc.—40 to 50%

Rum----produced from molasses Whisky---produced from cereals Brandy ----produced from Vodka------produced from potato

Undistilled alcoholAlcohol conc.---5 to 11%

Beer---produced from barley malt

Wine----- from fruit juice

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-

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

PROCESS OF METABOLISM IN BRIEF: Three vital organs are related to the metabolism of

alcohol as:1. liver2. Intestine3. stomatch But after being metabolized it affects the

entire body

REQUIREMENTS OF ALCOHOL METABOLISMENZYMES 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

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

GENES SUBUNITS

TISSUE DISTRIBUTION PROPERTIES

ADH1A alpha Most abundant in liver and adrenalglands. Much lower levelsin kidney, lung, colon, smallintestine, eye, ovary, bloodvessels. None in brain or heart.

Km of 0.02 to 5 mM for ethanol.Active only with ethanol

ADH1B beta same hereADH1C gamma same here ADH2 Primarily liver, lower levels in GI

tract.Km of 23 mM for ethanol

ADH3 pie Ubiquitously expressed, but athigher levels in liver. The onlyisozyme present in germinalcells.

Relatively inactive towardethanol (Km 3400 mM).Active mainly towardlong-chain alcohols

ADH4 delta Present in highest levels in upperGI tract, gingiva and mouth,esophagus, down to thestomach. Not present in liver.

Km of 58 mM. It is the mostactive of medium-chainalcohol dehydrogenases

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

-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.

METABOLIC PATHWAY:

-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

-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.

-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.

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.-

DRINKING HISTORY:The level of gastric ADH decreases and CYP2E1 increaseswith the progression from a naive, to a moderate, and to a heavy and chronicconsumer of alcohol.

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 thanthat of a man.

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.

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

TOXIC EFFECTS OF ALCOHOL METABOLISM

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.

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.

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.

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.

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 aminogroups, sulfhydryl groups, nucleotides, and phospholipids to form “adducts.”

DISEASES:1.alcohol induced hepatitis2.hepatic cirrhocis

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 diminishedsecretion of serum proteins and VLDL from the liver-

-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

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.

CIRROHTIC LIVER

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

CIRROHOTIC PATIENTS:

DIAGNOSIS:

Symptoms Blood test Medical history Physical examination A liver biopsy (small piece of liver tissue is removed and studied in the

lab)

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

How ever moderate amount of drinking is good for health

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