Ethanol

Question 1

What are the 2 steps of ethanol metabolism?

Answer 1

• Ethanol -> Acetaldehyde
  NAD+ -> NADH
  (Alcohol dehydrogenase)
• Acetaldehyde -> Acetate
  NAD+ -> NADH
  (Aldehyde dehydrogenase)

Question 2

Where does the first step of ethanol metabolism occur?

Answer 2

Cytosol

Question 3

Where does the second step of ethanol metabolism occur?

Answer 3

Mitochondria

Question 4

What are some problems caused by excessive ethanol consumption?

Answer 4

• CNS depressant - coma
• Hypoglycemia
• Ketone body formation (ketosis)
• Lactic acidosis
• Accumulation of fatty acids
• Hyperuricemia
• Hepatitis and cirrhosis

Question 5

What is the trigger for practically all biochemical problems associated with alcohol?

Answer 5

Increased NADH: NAD+ ratio

Question 6

What 2 enzymes can NADH inhibit in the TCA cycle?

Answer 6

• Isocitrate Dehydrogenase (Isocitrate -> a-ketoglutarate)
• Alpha-KG Dehydrogenase
  a-KG -> Succinyl-CoA

Question 7

What does NADH shunt oxaloacetate to?

Answer 7

Malate (generates NAD+)

Question 8

What enzyme converts Oxaloacetate to Malate?

Answer 8

Malate dehydrogenase (reversible)

Question 9

How does the shunting of Oxaloacetate to Malate generate ketones|?

Answer 9

Acetyl-CoA cannot bind with oxaloacetate to create citrate

• Shunted away from TCA cycle
• Instead Acetyl-CoA converted to ketones

Question 10

Describe how alcoholics get hypoglycemia?

Answer 10

• Oxaloacetate depleted (shunted to malate) which is involved in gluconeogenesis

Question 11

When is hypoglycemia posssible after drinking?

Answer 11

When glycogen stores are low as this is an important source of fasting glucose
- Drinking w/o eating
- Drinking after running
As these deplete glycogen stores

Question 12

What is acetate converted into in the liver?

Answer 12

Acetyl-CoA

Question 13

What other than acetate is converted to acetyl coA (and subsequently ketones, if NADH/NAD ratio is high)?

Answer 13

• Glucose
• Amino acids
• Fatty acids

Question 14

What enzyme leads pyruvate towards the TCA cycle and is inhibited by NADH?

Answer 14

Pyruvate dehydrogenase

Question 15

What does the conversion of pyruvate to lactate produce, why is this important in the context of alcohol?

Answer 15

Pyruvate -> Lactate

• Generates NAD+ (from NADH)
• Increased NAD+ which is depleted in ethanol metabolism

Question 16

How does alcohol cause an accumulation of fatty acids in the liver?

Answer 16

High levels of NADH stall Beta oxidation

• Beta oxidation generates NADH (like TCA cycle)
• Requires NAD+
• Inhibited when NADH is high
• Therefore decreased FA breakdown

Question 17

What molecule in the TCA cycle builds up in alcholol and can then be converted to fatty acids?

Answer 17

Citrate

• Will migrate from mitochondria to cytosol
• Can then be converted to fatty acids

Question 18

What is the rate limiting step/enzyme of fatty acid synthesis?

Answer 18

Acetyl-CoA Carboxylase (biotin cofactor)

Acetyl-CoA -> Malonyl-CoA

Question 19

What molecule enhnces Acetyl-CoA carboxylase?(rate-limiting enzyme of FA synthesis)

Answer 19

Citrate (slow TCA cycle)

Question 20

What molecule in fattty acid synthesis will inhibit Beta-oxidation?

Answer 20

Malonyl-CoA

Question 21

What will Malic enzyme generate (from malate)?

Answer 21

NADPH and Pyruvate

Question 22

What does NADPH favor?

Answer 22

Fatty acid synthesis (NADPH generated in alcoholism)

Question 23

What does fatty acid synthase require (generated from malate/malic acid synthase)?

Answer 23

NADPH

Question 24

What is palmitate generated from?

Answer 24

Acetyl CoA and malonyl CoA

• Requires NADPH
• Enzyme: Fatty acid synthase

Question 25

What does glycerol-3-Phosphate require to be converted into Dihydroxyacetone Phosphate?

Answer 25

NAD+ (depleted with alcohol) | - Enzyme: Glycerol-3-Phosphate Dehydrogenase

Question 26

What will a depletion of NAD+ cause to glycerol-e-phosphate levels?

Answer 26

Will increase G3P - Increased triglycerides - Fatty liver

Question 27

How can alcohol trigger gout?

Answer 27

- Urate and lactate compete for excretion in PCT | - Increased lactate results in decreased urate excretion

Question 28

What substance is toxic to liver cells and leads to alcoholic inflammation, hepatitis and cirrhosis?

Answer 28

Acetaldehyde - High NADH will slow its metabolsim to acetate - Build up occurs in alcoholics

Question 29

What substance leads to catecholamine release, fluching, palpitations, N/V?

Answer 29

Acetaldehyde

Question 30

What inhibits aldehyde dehydrogenase (builds up acetaldehyde)?

Answer 30

Disulfiram (antabuse)

Question 31

What deficiency causes alcoholic flushing?

Answer 31

Aldehyde dehydrogenase 2 (ALDH2)

Question 32

What cancers are at incr risk in Aldehyde dehydrogenase 2 (ALDH2) deficiency (asian flush)?

Answer 32

- Esophageal cancer | - Oropharyngeal cancer

Question 33

Wha substance inhibits alcohol dehydrogenase?

Answer 33

Fomepizol (antizol)

Question 34

What is Fomepizol used in?

Answer 34

- Methanol and ethylene glycol intoxication

Question 35

What toxic substances does alcohol dehydrogenase convert methnol and ethylene glycol into? (hence the use of feompeizol)

Answer 35

- Methanol - Formaldehyde | - Ethylene glycol - Glycoaldehyde

Question 36

What other metabolic pathway can lead to hepatitis and cirrhosis (not acetaldehyde buil-up)?

Answer 36

Microsomal ethanol-oxidising system (MEOS) | - Normally metabolises samll amount of ethanol but becomes important w. excessive consumption

Question 37

What molecules does Microsomal ethanol-oxidising system (MEOS) pathway consume?

Answer 37

- NADPH | - Oxygen

Question 38

What does Microsomal ethanol-oxidising system (MEOS) generate?

Answer 38

- Acetaldehyde - Acetate - Free radicals from oxygen consumption -> damage

Question 39

What does the consumption of NADPH from the Microsomal ethanol-oxidising system (MEOS) cause?

Answer 39

Glutathione which cannot be regenrated | - Loss of protection from oxidative stress -> liver hepatitis and cirrhosis

Question 40

What enzyme is Microsomal ethanol-oxidising system (MEOS) dependant on?

Answer 40

CYP450