Ethanol Metabolism B&B

Question 1

how is ethanol basically metabolized? (3 steps)

Answer 1

1. ethanol —> acetaldehyde via alcohol dehydrogenase (cytosol)
2. acetaldehyde moves it mitochondria
3. acetaldehyde —> acetate via aldehyde dehydrogenase (mitochondria)

*both steps produce NADH! (problem with excessive ethanol ingestion is a lotttt of NADH produced)

Question 2

what is the main problem with excessive ethanol ingestion?

Answer 2

tons of NADH produced via ethanol metabolism, which disrupts a lot of pathways

—> stalled TCA causes lactic acidosis, ketosis, hypoglycemia (decreased gluconeogenesis), increased fatty acid synthesis
—> stalled beta oxidation causes accumulation of fatty acids, fatty liver
—> hyperuricemia, gout (decreased uric acid excretion due to high plasma lactate)

Question 3

why does hypoglycemia occur with excessive ethanol intake?

Answer 3

ethanol metabolism produces a lot of NADH

excess NADH halts the TCA cycle, and oxaloacetate (substrate for gluconeogenesis) is shunted backwards to malate

decrease in gluconeogenesis —> hypoglycemia

glycogen is important source of fasting glucose, so drinking without eating or drinking after running can be dangerous!

Question 4

why does ketosis occur with excess ethanol intake?

Answer 4

ethanol metabolism produces a lot of NADH, which stalls TCA cycle

also produces acetate (via aldehyde dehydrogenase), which liver can convert to acetyl-CoA, which can then be shunted to ketone production (because TCA is stalled)

Question 5

why does excess ethanol intake cause an accumulation of fatty acids?

Answer 5

ethanol metabolism produces a lot of NADH

beta oxidation requires NAD+ and generates NADH —> so excessive ethanol intake inhibits beta oxidation and fatty acids accumulation —> fatty liver

Question 6

why does hepatitis/cirrhosis occur with excessive ethanol intake?

Answer 6

ethanol metabolism produces a lot of NADH, which slows the metabolism of further ethanol metabolism —> acetaldehyde builds up, which is hepatotoxic

—> acute alcoholic hepatitis, chronic cirrhosis

Question 7

what 3 enzyme systems are responsible for metabolism of ethanol in the liver?

Answer 7

1. cytosolic alcohol dehydrogenase (main mechanism)
2. microsomal ethanol oxidizing system (MEOS) in the smooth ER
3. catalase in peroxisomes

Question 8

what occurs from acetaldehyde toxicity as a result of excessive ethanol consumption?

Answer 8

ethanol —> acetaldehyde (via alcohol dehydrogenase, ADH)

acetaldehyde is peripheral vasodilator —> flushing, headache, sweating, increased HR, N/V, blurred vision

Question 9

what is the therapeutic use of disulfiram?

Answer 9

disulfiram: inhibits acetaldehyde dehydrogenase (ALDH), enzyme necessary for ethanol metabolism into acetate

used to treat chronic alcohol use disorder by causing unpleasant effects when alcohol is consumed

Question 10

_____ is an inducible enzyme of the microsomal ethanol oxidizing system (MEOS) in the smooth ER, an alternative metabolic pathway for ethanol (when main cytosolic ADH is overwhelmed)

Answer 10

CYP2E1 - unregulated with chronic alcohol consumption, metabolizes alcohol to acetaldehyde