Week 4 - Case Study: Drinking as a lifestyle Flashcards
After consumption, in what tissues does ethanol partition? What tissues exclude ethanol?
If have 70kg man and 70kg female, which will have higher blood alcohol content if each have 3 drinks?
What effects does ethanol have in brain?
Drink it, goes into mount and to GI tract and into blood then through first pass metabolism through liver and then through the rest of the body
Tissues that have a lot of water will take a lot of alcohol in
Excluded from fat and bone
The female. Because on average females have a higher fat content than males and will have less places for the alcohol to go
In brain GABA increases, Glutamate decreases
Describe the pathway(s) by which ethanol is metabolized. What are the products of ethanol metabolism? Draw it.
How do the Km’s compare for the two reactions?
What is the energy difference gaine from each pathway?
The first and major route uses alcohol dehydrogenase and acetaldehyde dehydrogenase, converting ethanol via acetaldehyde to acetate which is then converted to acetyl-CoA. NADH + H+ are produced in both of these reactions
The second route involves a microsomal cytochrome P450 (microsomal ethanol oxidizing system MEOS), also producing acetaldehyde, NADPH to NADP+, O2 to water
The Km for ADH is lower than the oxidase so this route metabolizes ethanol to acetaldehyde faster
Energy from ADH is 13 ATP
Form MEOS is 8 ATP
How do inherited mutations in ethanol metabolizing enzymes alter carriers’ susceptibility to alcoholism?
With ADH mutation you get a higher Vmax, this converts ETOH into acetaldehyde much quicker, thus accumulating acetaldehyde
With ALDH mutation, acetaldehyde builds up beacuase it isnt turned into acetyl CoA as fast, ie the metabolism of acetaldehyde to acetyl CoA is much slower
So with ALDH mutation, you would get accumulation of acetaldehyde – This makes people very sick and unpleasant.. So this will lower susceptibility to alcoholism
With ADH mutations that increase metabolism.. ETOH gets turned into acetaldehyde much quicker, acetaldehyde makes you feel bad so people with these mutations will also be less susceptible to alcoholism
What enzyme does disulfiram target? How does disulfiram promote abstinence from alcohol?
Disulfiram interferes with the hepatic oxidation of acetaldehyde by inhibiting the enzyme aldehyde dehydrogenase (ALDH)
Individuals taking disulfiram who drink small amounts of alcohol will have serum acetaldehyde concentrations 5-10 times higher than those pateints who are not taking desulfiram
Patients can experience a throbbing headache, dyspnea, throbbing in the neck, nausea, copious vomiting, diaphoresis, thirst, chest pain, palpitation, tachycardia, hypotension, blurred vision, vertigo, weakness, anxiety, syncope, and confusion
Describe the kinetics of the enzyme identified in Question #1 in the presence and absence of disulfiram. What is disulfiram’s mode of inhibition?
In absence of disulferam ALDH has a lower km than when disulferam is present – so it would shift the curve to the right with same Vmax (competitive inhibition) – discrepancy so will not be on the test.. If it bound to ALDH irriversibly the Vmax would be lowered.
It competes with nicotinamide adenine dinucleotide (NAD) for binding sites on aldehyde dehydrogenase.
Does disulfiram inhibit any other “off target” enzymes?
Yes. Dopamine Hydroxylase
The enzyme that catalyzes a reaction in the process of converting dopamine to norepinepherine
What receptor(s) does norepinephrine activate? What type(s) of cells express this receptor?
Norepinephrine acts predominantly on alpha-adrenergic receptors to produce constriction of resistance and capacitance vessels, thereby increasing systemic blood pressure and coronary artery blood flow
Describe the signal transduction pathway activated when norepinephrine binds its receptor. How did activation of this receptor help restore normal blood pressure in your patient?
What classification are norepinephrine and dopamine?
What extermal stimuli do they respond to?
catecholamines:
Act as both neurotransmitters and circulating hormones
Secreted in response to pain, hemorrhage, exercise, hypoxia and hypoglycemia
Activate the fight or flight response
increased cardiac output
mobilization of fuel stores
While you were considering options to resolve your patient’s hypotension, you briefly considered administering intravaneous dopamine, but you ultimately decided to give him norepinephrine instead. Would dopamine have been effective in restoring normal blood pressure in this patient? Why or why not?
Disulfiram inhibits Dopamine hydroxylase – converts dopamine to norepinepherine
So the reason he has low blood pressure is because disulfiram is inhibiting the conversion of dopamine to norepinepherine.. Giving more dopamine wouldn’t help…
How is serum triglyceride homeostasis normally maintained?
Fatty acid synthesis and beta oxidation of fatty acids
Triglycerides synthesized in liver. Liver exports them in VLDLs into blood for other cells to use. LPL (lipoprotein lipase) cleaves the fatty acids for uptake into cells
So you can either store fat or burn fat*
Can products of ethanol metabolism contribute to triglyceride production?
Yes. Products are NADH and acetyl CoA, both are used in fatty acid synthesis which would increase serum triglicerides
During episodes of hypertrigeleridemia, the patient’s serum cholesterol only rose modestly. Is this observation significant in suggesting an underlying cause of the hypertriglyceridemia?
The products of alcohol metabolism, acetyl CoA and NADH, will inhibit oxidation of fatty acid sythesis..
The peaks are first pass fat in chylomicrons.. They don’t have anywhere to go because oxidation is product inhibited so if they were being processed in liver there would be an increase of cholestrol in liver (but cholesterol synthesis is going to be inhibited)
NADH / NAD+ ratio… NADH production will be eleveted no matter if FED or FASTED state, the body needs to detoxify alcohol no matter what… So fatty acids are stored but not oxidized for fuel. Usually the fatty acids are stored in the liver so you get fatty liver disease… or get production of VLDL..
NADH / NAD+ ratio: The conversion of ethanol to acetate by ADH and ALDH results in reduction of two NAD+ to NADH + H+. This elevates the ratio of NADH to NAD+
What heppens to beta oxidation of fatty acids?
The β-oxidation of fatty acids is inhibited. (step 3)
Dietary fatty acids are stored, not oxidized for fuel.
fatty acids + glycerol-3-P -> triacylglycerol -> VLDL -> fatty liver
The glycerol 3-P is from glycolysis
NADH / NAD+ ratio: The conversion of ethanol to acetate by ADH and ALDH results in reduction of two NAD+ to NADH + H+. This elevates the ratio of NADH to NAD+
How does this effect the TCA cycle?
Flux through the TCA cycle is inhibited.
Acetyl CoA is directed towards ketone body synthesis rather than citrate synthesis.
Pyruvate is directed towards lactate synthesis rather than acetyl CoA.
How does ethanol metabolism contribute to illness?
(in regards to acetaldehyde (tubuin))
Acetaldehyde is a reactive molecule which can bind DNA and proteins to form adducts which interfere with mitochondrial metabolism, DNA repair and DNA replication.
a. Example: acetaldehyde can impair function of tubulin.
IN LIVER CELLS
proteins exported form cell are synthesized in ER to Golgi to vesicles that ride tubulin to membrane, then released to extracellular space..
Acealdehyde damages tubulin, liver cannot rid proteins it makes
This causes osmotic imbalance, hepatocytes swell with water, can lead to rupture
What other ways can acetaldehyde harm body (ALDH2 and reactive O2 species)?
Acetaldehyde can form adducts on mitochondrial proteins and uncouple the electron transport chain, leading to increased reactive oxygen species production and further damage to mitochondrial enzymes such as ALDH2, preventing conversion of acetaldehyde to acetate
