Alcohol Metabolism - RM Flashcards
How many steps is ethanol metabolism and where does it occur?
2 steps, liver
What oxidizes ethanol to acetaldehye and NADH? Where in the cell does this reaction occur?
ADH, in the cytosol
What is important about acetaldehyde?
it’s toxic, so you don’t want it to build up in the cell
What is the second step of alcohol metabolism? What catalyzes it and where in the cell does it occur?
oxidation of acetaldehyde to acetate and NADH by ALDH in the mitochondria
What happens to acetate at the end of alcohol metabolism?
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
What helps with ethanol metabolism when ethanol in blood is high?
microsomal alcohol oxidizing system (MEOS) in liver
What enzymes function in the MEOS?
cytochrome P450 enzymes (CYP2E1 especially)
What are the products of MEOS?
acetaldehyde and reactive oxygen species
How is ethanol absorbed into the body?
by passive diffusion in the intestine
Where is a small percentage of ethanol metabolized rather than entering the blood?
gastric mucosal cells in the upper GI tract
Does ALDH have low Km or high Km for acetaldehyde?
low Km, it has high binding affinity
What is the highest affinity ADH isozyme for ethanol? Where is it primarily found?
ADH 1, found primarily in liver
Where are ADH4 isozymes? When are they active? What may they contribute to the risk of?
upper GI tract, active at high ethanol concentration, may contribute to risk of gastric cancer for heavy drinkers
Where is ADH2 isozyme found? When is it recruited to ethanol metabolism?
liver and lower GI, recruited at higher ethanol concentrations because it has a higher Km than ADH1
Where is ADH3? What is important about it?
many tissues, does not oxidize ethanol, active towards long chain alchols
Where is ALDH1 and where is ALDH2?
ALDH1- cytosol
ALDH2- mitochondria
What does accumulation of acetaldehyde due to inactive ALDH2 cause?
flushing, nausea, vomiting, distaste for alcoholic beverages
What is ALDH2*2? What does it cause?
- 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
Why are alcoholics treated with disulfiram?
it’s an ALDH inhibitor, so when they drink, acetaldehyde builds up and make them feel crappy
Where in the cell is acetyl coA synthetase I, what organ is this in? ACS II, what organ is this in?
ACS I- cytosolic, in liver
ACS II- mitochondrial, in heart and skeletal muscle
What does ACS I in the cytosol of the liver do? What is it regulated by?
generates acetyl coA for FA and cholesterol synthesis, regulated by cholesterol and insulin
Where does acetyl coA generated by ACS II go?
enters citric acid cycle and oxidized to CO2
What is the reaction in MEOS?
ethanol and NADPH both donate an electron to reduce O2 to water
What are the functions of the 2 catalytic components of cytP450?
cytP450 reductase–transfers electron via FAD and FMN from NADPH
cytochrome P450- contains binding sites for O2 and ethanol to carry out the reaction
Which cytP450 enzyme has the highest affinity for ethanol?
CYP2E1
What induces CYP2E1 expression 5-10 fold?
chronic alcohol consumption stabilizes CYP2E1, protects it against degradation and increases the transcription of it
How does CYP2E1 expression increase harm the cell?
increases ethanol clearance, which produces acetaldehyde faster than it can be metabolized by ALDH leading to damage to liver by acetaldehyde and ROS
What do acetaldehyde and ROS cause?
lipid peroxidation, protein damage, mitochondrial dysfunction, DNA damage
How does drinking history affect ethanol metabolism?
gastric ADH decreases and CYP2E1 increases as you become more of an alcoholic
Why do women have higher blood ethanol levels for the same amount of alcohol?
lower gastric ADH activity, smaller water space and size
What are the acute effects of ethanol ingestion due to?
increase in NADH/NAD ratio
What are chronic effects of ethanol consumption due to?
acetaldehyde and reactive oxygen species
How does NADH/NAD ratio affect lipid metabolism in liver?
inhibits FA oxidation and citric acid cycle, leading to accumulation of free FAs and TG synthesis
How does NADH/NAD increase TG synthesis?
increases G3P levels and liver acyltransferase levels as well as FA levels, causing them all to reform TGs
Why does ketogenesis occur as a result of NADH/NAD ratio?
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
How does lactic acidosis occur from NADH/NAD ratio increase?
very high NADH/NAD increases production of lactate by lactate dehydrogenase from pyruvate to use up the NADH
Why are people with gout recommended not to drink?
increase in blood lactate decreases uric acid excretion
What does conversion of pyruvate to lactate cause?
hypoglycemia in fasting state because lactate can’t enter gluconeogenesis
Why shouldn’t you take phenobarbital and drink at the same time?
drinking inhibits CYP2B2 that inactivates phenobarbital causing phenobarbital to accumulate
What does acetaldehye forming adducts with amino acids cause? with GSH? with microtubules?
with amino acids–decreased protein synthesis
with GSH–decreased protection against oxidative stress
with microtubules–decreased secretion of plasma proteins and VLDLs from liver
What does the accumulation of proteins in the liver from the inability to secrete them because of acetaldehyde-microtubule adducts cause?
causes water to enter hepatocytes–>swelling of liver–> portal hypertension
What does peroxidation of lipids in the inner mitochondrial membrane and oxidative damage to membrane proteins by acetaldehyde inhibit?
inhibits electron transport and acetaldehyde conversion to acetate since ALDH2 is a membrane-associated protein
What is fibrosis? What does it progress to?
overproduction of extracellular matrix and connective tissue in wound-healing like repsonse to insult, leads to sclerosis
What is scleorsis?
degeneration of ECM components
What is cirrhosis?
end stage process of liver fibrotic degneration
What is Laerinec cirrhosis?
as liver function is lost, liver shrinks
Why is there an accumulation of bilirubin and ammonia in blood with cirrhosis?
liver lost ability to conjugate and secrete bilirubin or incorporate amino groups into urea
What does accumulation of bilirubin cause?
jaundice
