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Biochemistry GI > Alcohol Metabolism > Flashcards

Alcohol Metabolism Flashcards

1
Q

1st reaction of the 2 step pathway of EtOH metabolism

A

EtOH is oxidized in cytosol of hepatocytes

enzyme: alcohol dehydrogenase (ADH)
* ADH1 has highest specificity for EtOH out all the 7 isoenzymes

Products: NADH, H+ + acetaldehyde

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2
Q

ADH4

A

isoenzyme present in upper GI tract

could contribute to GI cancer associated with excessive alcohol intake

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3
Q

acetaldehyde dehydrogenase (ALDH)

A

2nd reaction of EtOH metabolic pathway

acetaldehyde enters the mitochondria to be oxidized

products = acetate + NADH

major isoenzyme = ALDH2***

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4
Q

fate of the acetate in EtOH metabolism

A

most enters the bloodstream, where it can be taken up by extrahepatic tissues

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5
Q

fate of acetaldehyde in EtOH metabolism

A

most will be converted to acetate in liver mitochondria

some can be excreted into bloodstream = toxic

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6
Q

acetyl-CoA Synthase

A

Acetate –> AcCoA

mitochondria in extrahepatic tissues (like muscle)

–> CAC

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7
Q

microsomal ethanol oxidizing system (MEOS)

A

activated when EtOH levels are too high to be handled by just ADH and ALDH

located in the ER of liver cells

enzyme = cytochrome p450 family of enzymes

when activated, can metabolize 10-20% of EtOH –> acetaldehyde

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8
Q

MEOS reaction (cytochrome p450)

A

‘mixed function oxidase’ reaction

both EtOH and NADPH get oxidized by donating their electrons to O2

products = acetaldehyde, water, and NAD+

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9
Q

locus of cytochrome p450

A

CYP2E1

much higher Km for EtOH than ADH –> why not expressed under lower [EtOH]

chronic alcohol use can increase CYP2E1 expression in liver cells by 5-10 fold

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10
Q

negative consequences of MEOS reaction

A
  1. in acetaldehyde is produced faster than ALDH can oxidize it –> risk of tissue damage
  2. p450 enzymes are capable of producing ROS
  3. certain drugs (Barbiturates) are consumed with excess alcohol –> then EtOH uses up all the p450 and can overdose on the drug
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11
Q

ADH1B*1 polymorphism

A

less active isoform of ADH1

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12
Q

homozygous ADH1B1/1B1 polymorphism

A

risk to develop Wernicke-Korsakoff syndrome

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13
Q

acute toxic effects of EtOH metabolism

A

due to ADH and ALDH reactions

build up of NADH (increases NADH:NAD+)

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14
Q

chronic toxic effects of EtOH metabolism

A

acetaldehyde and ROS production

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15
Q

consequence of increase NADH:NAD+

general

A

many important dehydrogenase reactions become inhibited and sometimes even reverse
–> so important pathways inhibited or inappropiately activated

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16
Q

consequence of excessive EtOH metabolism

specific (9 things)

A
  1. increased NADH:NAD+ imbalance
  2. (-) glycolysis and beta-oxidation
  3. (+) TG synthesis –> increase [VLDL], hyperlipidemia, and hepatic steatosis
  4. depletion of OAA and (-) CAC
  5. (+) ketogenesis –> ketoacidosis
  6. pyruvate –> lactate –> lactic acidemia
  7. (-) urate excretion –> gout like symptoms
  8. (-) using glucogenic amino acids –> hypoglycemia
  9. interference with drug metabolism
17
Q

inhibition of glycolysis by EtOH metabolism

A

step 6 in glycolysis

Reaction: glyceraldehyde-3P –> 1,3-BP (NAD+ –> NADH)

enzyme: glyceraldehyde-3P-dehydrogenase

inhibited due to low NAD+ levels

reversed by high NADH

18
Q

(-) beta-oxdiation by EtOH metabolism

A

3rd reaction in beta-ox

reaction: hydroxyacyl-CoA –> ketoacyl-CoA (NAD+ –> NADH)
enzyme: beta-hydroxyacly-CoA dehydrogenase

inhibited by low NAD+….

19
Q

(+) TG synthesis by EtOH metabolism

A

due to Glyceraldehyde-3P DH being inhibited in glycolysis…

Glyceraldehyde-3P is converted to DHAP

high NADH:NAD+ then stimulates…

DHAP –> glycerol-3P

enzyme: glycerol-3P dehydrogenase

***reaction is seen in the gylcerol phosphate shuttle, used to move NADH reducing equivalents from cytosol into mitochonria

20
Q

Fatty acyl-CoA transport (carnitine shuttle)

due to EtOH metabolism

A

slows down as a result of beta-oxidation inhibition

therefore…

cytosolic FAs and glycerol-3P combine to form TGs

TGs –> VLDL –> hyperlipidemia or fatty liver if not secreted into blood

21
Q

(-) CAC by EtOH metabolism

A 
last reaction (malate --> OAA)
**also part of the malate-aspartate shuttle, used to move NADH equivalents from cytoplasm to mitochondria

malate dehydrogenase

inhibited and reversed due to high NADH: NAD+ so get a depletion of OAA also…

22
Q

ketogenesis due to EtOH metabolism

A

since malate –> OAA is inhibited and reversed

Acetyl-CoA is redirected to instead produce ketone bodies

23
Q

lactic acidemia by EtOH metabolism

A

gluconeogensis is inhibited by NADH:NAD+ imbalance

so pyruvate redirected to be converted into lactate

enzyme: lactate dehydrogenase

24
Q

uric acid excretion by EtOH metabolism

A

decreased

due to build up of lactate (lactic acidemia)

lactate and urate use same excreting transporters –> less urate in urine and more in blood

gout like symptoms persist

25
Q

hangover symptoms

A

build up of acetaldehyde and ROS

Biochemistry GI (6 decks)

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