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U6 MCP > Alcohol Metabolism - RM > Flashcards

Alcohol Metabolism - RM Flashcards

1
Q

How many steps is ethanol metabolism and where does it occur?

A

2 steps, liver

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2
Q

What oxidizes ethanol to acetaldehye and NADH? Where in the cell does this reaction occur?

A

ADH, in the cytosol

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3
Q

What is important about acetaldehyde?

A

it’s toxic, so you don’t want it to build up in the cell

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4
Q

What is the second step of alcohol metabolism? What catalyzes it and where in the cell does it occur?

A

oxidation of acetaldehyde to acetate and NADH by ALDH in the mitochondria

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5
Q

What happens to acetate at the end of alcohol metabolism?

A

acetate enters the blood, travels to muscles and other tissues where it is converted to acetyl coA by acetyl coA synthetase to be used for energy

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6
Q

What helps with ethanol metabolism when ethanol in blood is high?

A

microsomal alcohol oxidizing system (MEOS) in liver

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7
Q

What enzymes function in the MEOS?

A

cytochrome P450 enzymes (CYP2E1 especially)

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8
Q

What are the products of MEOS?

A

acetaldehyde and reactive oxygen species

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9
Q

How is ethanol absorbed into the body?

A

by passive diffusion in the intestine

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10
Q

Where is a small percentage of ethanol metabolized rather than entering the blood?

A

gastric mucosal cells in the upper GI tract

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11
Q

Does ALDH have low Km or high Km for acetaldehyde?

A

low Km, it has high binding affinity

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12
Q

What is the highest affinity ADH isozyme for ethanol? Where is it primarily found?

A

ADH 1, found primarily in liver

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13
Q

Where are ADH4 isozymes? When are they active? What may they contribute to the risk of?

A

upper GI tract, active at high ethanol concentration, may contribute to risk of gastric cancer for heavy drinkers

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14
Q

Where is ADH2 isozyme found? When is it recruited to ethanol metabolism?

A

liver and lower GI, recruited at higher ethanol concentrations because it has a higher Km than ADH1

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15
Q

Where is ADH3? What is important about it?

A

many tissues, does not oxidize ethanol, active towards long chain alchols

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16
Q

Where is ALDH1 and where is ALDH2?

A

ALDH1- cytosol

ALDH2- mitochondria

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17
Q

What does accumulation of acetaldehyde due to inactive ALDH2 cause?

A

flushing, nausea, vomiting, distaste for alcoholic beverages

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18
Q

What is ALDH2*2? What does it cause?

A
  • single AA substitution leads to allelic variant with 23 fold higher Km and 35 fold lower vmax (less affinity)
  • homozygosity protects against alcoholism because it sucks so hard when you drink that you dont want to
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19
Q

Why are alcoholics treated with disulfiram?

A

it’s an ALDH inhibitor, so when they drink, acetaldehyde builds up and make them feel crappy

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20
Q

Where in the cell is acetyl coA synthetase I, what organ is this in? ACS II, what organ is this in?

A

ACS I- cytosolic, in liver

ACS II- mitochondrial, in heart and skeletal muscle

21
Q

What does ACS I in the cytosol of the liver do? What is it regulated by?

A

generates acetyl coA for FA and cholesterol synthesis, regulated by cholesterol and insulin

22
Q

Where does acetyl coA generated by ACS II go?

A

enters citric acid cycle and oxidized to CO2

23
Q

What is the reaction in MEOS?

A

ethanol and NADPH both donate an electron to reduce O2 to water

24
Q

What are the functions of the 2 catalytic components of cytP450?

A

cytP450 reductase–transfers electron via FAD and FMN from NADPH
cytochrome P450- contains binding sites for O2 and ethanol to carry out the reaction

25
Q

Which cytP450 enzyme has the highest affinity for ethanol?

A

CYP2E1

26
Q

What induces CYP2E1 expression 5-10 fold?

A

chronic alcohol consumption stabilizes CYP2E1, protects it against degradation and increases the transcription of it

27
Q

How does CYP2E1 expression increase harm the cell?

A

increases ethanol clearance, which produces acetaldehyde faster than it can be metabolized by ALDH leading to damage to liver by acetaldehyde and ROS

28
Q

What do acetaldehyde and ROS cause?

A

lipid peroxidation, protein damage, mitochondrial dysfunction, DNA damage

29
Q

How does drinking history affect ethanol metabolism?

A

gastric ADH decreases and CYP2E1 increases as you become more of an alcoholic

30
Q

Why do women have higher blood ethanol levels for the same amount of alcohol?

A

lower gastric ADH activity, smaller water space and size

31
Q

What are the acute effects of ethanol ingestion due to?

A

increase in NADH/NAD ratio

32
Q

What are chronic effects of ethanol consumption due to?

A

acetaldehyde and reactive oxygen species

33
Q

How does NADH/NAD ratio affect lipid metabolism in liver?

A

inhibits FA oxidation and citric acid cycle, leading to accumulation of free FAs and TG synthesis

34
Q

How does NADH/NAD increase TG synthesis?

A

increases G3P levels and liver acyltransferase levels as well as FA levels, causing them all to reform TGs

35
Q

Why does ketogenesis occur as a result of NADH/NAD ratio?

A

acetyl coA that is generated can’t enter citric acid cycle since that is inhibited by the increased NADH/NAD ratio so it gets shunted to ketone body synthesis

36
Q

How does lactic acidosis occur from NADH/NAD ratio increase?

A

very high NADH/NAD increases production of lactate by lactate dehydrogenase from pyruvate to use up the NADH

37
Q

Why are people with gout recommended not to drink?

A

increase in blood lactate decreases uric acid excretion

38
Q

What does conversion of pyruvate to lactate cause?

A

hypoglycemia in fasting state because lactate can’t enter gluconeogenesis

39
Q

Why shouldn’t you take phenobarbital and drink at the same time?

A

drinking inhibits CYP2B2 that inactivates phenobarbital causing phenobarbital to accumulate

40
Q

What does acetaldehye forming adducts with amino acids cause? with GSH? with microtubules?

A

with amino acids–decreased protein synthesis
with GSH–decreased protection against oxidative stress
with microtubules–decreased secretion of plasma proteins and VLDLs from liver

41
Q

What does the accumulation of proteins in the liver from the inability to secrete them because of acetaldehyde-microtubule adducts cause?

A

causes water to enter hepatocytes–>swelling of liver–> portal hypertension

42
Q

What does peroxidation of lipids in the inner mitochondrial membrane and oxidative damage to membrane proteins by acetaldehyde inhibit?

A

inhibits electron transport and acetaldehyde conversion to acetate since ALDH2 is a membrane-associated protein

43
Q

What is fibrosis? What does it progress to?

A

overproduction of extracellular matrix and connective tissue in wound-healing like repsonse to insult, leads to sclerosis

44
Q

What is scleorsis?

A

degeneration of ECM components

45
Q

What is cirrhosis?

A

end stage process of liver fibrotic degneration

46
Q

What is Laerinec cirrhosis?

A

as liver function is lost, liver shrinks

47
Q

Why is there an accumulation of bilirubin and ammonia in blood with cirrhosis?

A

liver lost ability to conjugate and secrete bilirubin or incorporate amino groups into urea

48
Q

What does accumulation of bilirubin cause?

A

jaundice

U6 MCP (26 decks)

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