Ethanol Flashcards
What are the 2 steps of ethanol metabolism?
- Ethanol -> Acetaldehyde
NAD+ -> NADH
(Alcohol dehydrogenase) - Acetaldehyde -> Acetate
NAD+ -> NADH
(Aldehyde dehydrogenase)
Where does the first step of ethanol metabolism occur?
Cytosol
Where does the second step of ethanol metabolism occur?
Mitochondria
What are some problems caused by excessive ethanol consumption?
- CNS depressant - coma
- Hypoglycemia
- Ketone body formation (ketosis)
- Lactic acidosis
- Accumulation of fatty acids
- Hyperuricemia
- Hepatitis and cirrhosis
What is the trigger for practically all biochemical problems associated with alcohol?
Increased NADH: NAD+ ratio
What 2 enzymes can NADH inhibit in the TCA cycle?
- Isocitrate Dehydrogenase (Isocitrate -> a-ketoglutarate)
- Alpha-KG Dehydrogenase
a-KG -> Succinyl-CoA
What does NADH shunt oxaloacetate to?
Malate (generates NAD+)
What enzyme converts Oxaloacetate to Malate?
Malate dehydrogenase (reversible)
How does the shunting of Oxaloacetate to Malate generate ketones|?
Acetyl-CoA cannot bind with oxaloacetate to create citrate
- Shunted away from TCA cycle
- Instead Acetyl-CoA converted to ketones
Describe how alcoholics get hypoglycemia?
- Oxaloacetate depleted (shunted to malate) which is involved in gluconeogenesis
When is hypoglycemia posssible after drinking?
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
What is acetate converted into in the liver?
Acetyl-CoA
What other than acetate is converted to acetyl coA (and subsequently ketones, if NADH/NAD ratio is high)?
- Glucose
- Amino acids
- Fatty acids
What enzyme leads pyruvate towards the TCA cycle and is inhibited by NADH?
Pyruvate dehydrogenase
What does the conversion of pyruvate to lactate produce, why is this important in the context of alcohol?
Pyruvate -> Lactate
- Generates NAD+ (from NADH)
- Increased NAD+ which is depleted in ethanol metabolism
How does alcohol cause an accumulation of fatty acids in the liver?
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
What molecule in the TCA cycle builds up in alcholol and can then be converted to fatty acids?
Citrate
- Will migrate from mitochondria to cytosol
- Can then be converted to fatty acids
What is the rate limiting step/enzyme of fatty acid synthesis?
Acetyl-CoA Carboxylase (biotin cofactor)
Acetyl-CoA -> Malonyl-CoA
What molecule enhnces Acetyl-CoA carboxylase?(rate-limiting enzyme of FA synthesis)
Citrate (slow TCA cycle)
What molecule in fattty acid synthesis will inhibit Beta-oxidation?
Malonyl-CoA
What will Malic enzyme generate (from malate)?
NADPH and Pyruvate
What does NADPH favor?
Fatty acid synthesis (NADPH generated in alcoholism)
What does fatty acid synthase require (generated from malate/malic acid synthase)?
NADPH
What is palmitate generated from?
Acetyl CoA and malonyl CoA
- Requires NADPH
- Enzyme: Fatty acid synthase
What does glycerol-3-Phosphate require to be converted into Dihydroxyacetone Phosphate?
NAD+ (depleted with alcohol)
- Enzyme: Glycerol-3-Phosphate Dehydrogenase
What will a depletion of NAD+ cause to glycerol-e-phosphate levels?
Will increase G3P
- Increased triglycerides
- Fatty liver
How can alcohol trigger gout?
- Urate and lactate compete for excretion in PCT
- Increased lactate results in decreased urate excretion
What substance is toxic to liver cells and leads to alcoholic inflammation, hepatitis and cirrhosis?
Acetaldehyde
- High NADH will slow its metabolsim to acetate
- Build up occurs in alcoholics
What substance leads to catecholamine release, fluching, palpitations, N/V?
Acetaldehyde
What inhibits aldehyde dehydrogenase (builds up acetaldehyde)?
Disulfiram (antabuse)
What deficiency causes alcoholic flushing?
Aldehyde dehydrogenase 2 (ALDH2)
What cancers are at incr risk in Aldehyde dehydrogenase 2 (ALDH2) deficiency (asian flush)?
- Esophageal cancer
- Oropharyngeal cancer
Wha substance inhibits alcohol dehydrogenase?
Fomepizol (antizol)
What is Fomepizol used in?
- Methanol and ethylene glycol intoxication
What toxic substances does alcohol dehydrogenase convert methnol and ethylene glycol into? (hence the use of feompeizol)
- Methanol - Formaldehyde
- Ethylene glycol - Glycoaldehyde
What other metabolic pathway can lead to hepatitis and cirrhosis (not acetaldehyde buil-up)?
Microsomal ethanol-oxidising system (MEOS)
- Normally metabolises samll amount of ethanol but becomes important w. excessive consumption
What molecules does Microsomal ethanol-oxidising system (MEOS) pathway consume?
- NADPH
- Oxygen
What does Microsomal ethanol-oxidising system (MEOS) generate?
- Acetaldehyde
- Acetate
- Free radicals from oxygen consumption -> damage
What does the consumption of NADPH from the Microsomal ethanol-oxidising system (MEOS) cause?
Glutathione which cannot be regenrated
- Loss of protection from oxidative stress -> liver hepatitis and cirrhosis
What enzyme is Microsomal ethanol-oxidising system (MEOS) dependant on?
CYP450
