Unit 6 - Alcohol Metabolism Flashcards Preview

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Flashcards in Unit 6 - Alcohol Metabolism Deck (26):

what is the simple 2 step process that happens to ingested ethanol? where is and what does this?

most of this happens in the liver, and generates NADH in both steps to substantially increase NADH:NAD ratio
1. oxidation of ethanol to acetaldehyde (toxic) via alcohol dehydrogenase (ADH) in cytosol
2. oxidation of acetaldehyde to acetate via acetaldehyde dehydrogenase (ALDH) in mitochonria


what happens after ethanol is metabolized in the liver?

byproduct acetate enters blood and travels to muscle and other tissues, where it's converted to ACoA via acetyl CoA synthetase, and enters the TCA cycle or FA synthesis


what is the solubility of ethanol? where is it usually absorbed?

small molecule soluble in water and lipid
-absorbed from intestine by passive diffusion
--0-5% enters gastric mucosa in upper GIT and metabolized
--85-98% enters blood and metabolized in liver, or 2-10% excreted thru lungs/kidneys


what happens to acetaldehyde in ethanol metabolism?

it's made in cytosol of liver cells from ADH, making NADH
-90% is metabolized via ALDH, but 10% can damage liver or enter blood to exert toxic effects on other tissues


what is the Km of ALDH and what does this mean?

Km is low, meaning it has high affinity and is preferentially chosen to break down acetaldehyde no matter the [alcohol]
-however, when [alcohol] is high, MEOS will use it instead


what is MEOS? what does it do? where is it?

microsomal alcohol oxidizing system (made of all cytochrome P450 enzymes, mostly CYP2E1)
-located in ER
-10-20% of ingested alcohol is oxidized via this route for a moderate drinker
-uses NADPH and O2 to break ethanol into acetaldehyde and 2H2O


what are the ADH isozymes? which have the lowest Km?

differ in specificity of chain length of alcohol substrate
-ADH1 family (alpha/beta/gamma) has highest affinity (lowest Km)
--can form homodimers or heterodimers with each other, but not ADH2-4


where are ADH1/2/3/4 found? what are their specifics?

1: found in very high quantities in liver (3% of soluble PRO) so called "liver ADH"
-since high affinity binding of ethanol, liver is major site of ethanol metabolism
2: liver and lower GIT
3: ubiquitous, but higher in liver, and only one in germinal cells
-inactive towards ethanol, but active toward long chain alcohols
4. upper GIT, gingiva, mouth, esophagus, and stomach, but NOT in liver, so gastric ADH
-at high ethanol concentration, conversion may contribute to risk of cancer in heaviest drinkers
-most active medium-chain alcohol dehydrogenases toward retinal


what are the ALDH isozymes? their structures?

>80% of acetaldehyde oxidation is done by mitochondrial ALDH2 (high affinity, low Km)
-the remainder is done by cytoplasmic ALDH1
-both are tetramers with individual subunits containing 499-500 AA


what happens if there's inactive ALDH2?

accumulation of acetaldehyde causes flushing, nausea, vomiting, and distaste for alcohol
-a single AA substitution (glu to lys at residue 487) creates variant ALDH2*2, which has 23-fold higher Km (lower affinity) and 35-fold lower Vmax
-homozygosity provides absolute protection VS alcoholism, b/c of all the negatives


what effect do ALDH inhibitors have on alcoholics? what happens if they keep drinking?

treat alcoholics with them (ex: disulfiram) to make them abstain
-if keep drinking, the elevated acetaldehyde can damage the liver


what does acetyl CoA synthetase do? isoforms? where are they? what are its products?

ACSI - primary isoform in liver; cytosolic enzyme that makes ACoA for cholesterol and FA synthesis
-acetate entry here is regulated by cholesterol and insulin, so most acetate enters blood
ACSII - mitochondrial enzyme in other tissues, such as heart and skeletal muscle, in high concentrations
-ACoA generated can enter TCA cycle and be oxidized to CO2

needs CoA-SH and ATP to make ACoA + AMP + PPi


what are the 2 major catalytic components of the cytochrome P450 superfamily?

1. cytochrome P450 reductase - transfers electrons (via FAD and FMN) from NADPH
2. cytochrome P450 that has binding sites for O2 and substrate (ex: ethanol) and carries out RXN


what is the most important cytochrome of cytochrome P450?

-2 is the gene family
-E is subfamily
-1 is individual enzyme in subfamily
has the highest activity compared to other P450s, but only when chronic and/or high levels of alcohol


how do products of ADH compare to MEOS?

ADH uses ethanol and NAD+ to make acetaldehyde and NADH

MEOS uses ethanol and NADPH to make acetaldehyde and NADP+, along with ROS for oxidative stress and cellular damage


what does chronic consumption of alcohol induce?

induces expression of CYP2E1 5-10 fold, via stabilization of protein and protection VS degradation
-this increases ethanol clearance from blood, but produces acetaldehyde faster than it can be metabolized by ALDH, causing damage to liver and other tissues


how can ethanol metabolism vary via...
-drinking history
-quantity of ethanol

1. different polymorphic forms of ADHs and ALDHs can effect ethanol oxidation and acetaldehyde accumulation
-different allelic variants of CYP2E1 can vary activity greater than 20-fold
2. level of gastric ADH decreases, and CYP2E1 increases with progression from naive to moderate to heavy and chronic
3. women have lower gastric ADH activity, size, and 12% smaller water space leading to higher blood levels of ethanol
4. higher quantity causes greater involvement of CYP2E1 and higher levels of acetaldehyde and ROS


what are the reversible VS irreversible acute effects on liver metabolism from alcohol?

reversible: inhibition of FA oxidation, and stimulation of TAG synthesis causing fatty liver; ketoacidosis or lactic acidosis causing hypo/hyperglycemia (depends on dietary state)

irreversible: acetaldehyde and ROS cause alcohol-induced hepatitis (liver inflammation, necrotic cell death), or cirrhosis (damage to hepatocytes from fibrosis, altered blood flow, and loss of liver function)


what are the 9 acute effects of ethanol metabolism on the liver's lipid metabolism?

1. increased NADH/NAD+ ratio
2. high ratio inhibits FA oxidation and TCA cycle, so accumulation of FFA
3. FA are re-esterified to G3P by acyltransferases in ER of liver, making TAGs that are converted to VLDLs that enter liver and blood to cause hepatic steatosis and lipidemia
4. oxidized FA are converted to ACoA and ketone bodies (acetoacetate and beta-hydroxybutyrate), since TCA cycle is inhibited
5. entry into ketone body pathway raises levels to cause ketoacidosis
6. high ratio causes increased production of lactate via lactate dehydrogenase to cause lactic acidosis/acidemia
7. increased blood lactate decreases uric acid excretion by kidney (drinking is contraindicated in gout)
8. lactate is made at expense of pyruvate, so alanine that makes pyruvate is converted to lactate so can't enter gluconeogenesis
9. ethanol inhibits certain CYP2B2 that metabolizes bartibuates, so if alcohol + barbituates, will have increased toxic levels


what's the difference between drinking alcohol during a meal or not?

fed: causes transient hyperglycemia, b/c high NADH/NAD+ ratio inhibits glycolysis at glyceraldehyde-3-P dehydrogenase step

fast: causes hypoglycemia, b/c high NADH/NAD+ ratio causes alanine that turns into pyruvate to be converted to lactate (cannot enter gluconeogenesis)


what are the 6 effects of chronic alcohol consumption on the liver?

1. increased acetaldehyde forms adducts with AA (amino and sulfhydryl groups), PRO, nucleotides, and PLs to cause decreased PRO synthesis
2. acetaldehyde forms adduct with GSH and other antioxidants, so can't protect VS ROS
3. induction of MEOS increases ROS production, lipid peroxidation, and cell damage
4. peroxidation of lipids in IMM, and oxidative damage to PRO inhibits ETC and diminishes acetaldehyde conversion to acetate
5. adduct formation with PRO causes loss of function
-with tubulin will decrease secretion of plasma PRO and VLDL from liver
-many PRO normally secreted into blood will accumulate in liver
6. accumulation of PRO causes H2O to enter hepatocytes, causing liver swelling, portal hypertension, disruption of hepatic architecture; cell damage releases ALT and AST


what are the levels of hepatic injury?

cirrhosis - 20% of heavy drinkers progress from fibrosis to cirrhosis



increase of connective tissue ("wound-healing-like reaction)
-accumulation and crossing of both fibrillar and basement membrane-like collagens
-increased laminin and fibronectin
-thickening of CT septae
-capillary formation w/in sinusoids



aging of fibrotic tissue (degeneration of components of ECM)
-decreased hyaluronic acid and heparan sulfate proteoglycans
-increased chondroitin sulfate progeoglycans
-progressive fragmentation and disappearance of elastic fibers
-distortion of sinusoidal architecture and parenchymal damage



end-stage process of liver fibrotic degeneration
-whole liver is heavily distorted by thick bands of collagen surrounding nodules of hepatocytes with regenerative foci
-irreversible liver damage
-as liver function is lost, it becomes shrunken (Laennec cirrhosis)


what are loss of metabolic functions in Laennec cirrhosis?

-PRO synthesis/secretion
-ability to incorporate amino groups into urea (causes toxic ammonia, less conjugation, and bilirubin secretion)
--increased blood bilirubin is deposited in many tissues (skin, sclera) to cause jaundice