MCP Lecture 4 Flashcards
How and where is ethanol most commonly metabolized?
ethanol –> acetaldehyde (production of NADH) in cytosol by alcohol dehydrogenase (ADH)
acetaldehyde –> acetate (production of NADH) in mitochondria by acetaldehyde dehydrogenase (ALDH)
What happens with acetate from ethanol metabolism?
enters the blood and travels to muscle and other tissues where it converted to acetyl CoA by acetyl CoA synthetase and is oxidized by the Krebs cycle
How is ethanol absorbed in the intestine?
passive diffusion
What is the other route for alcohol metabolism in the liver?
MEOS located in the ER of liver cells
converted by CYP2E1 (ethanol –> acetaldehyde using NADPH)
10-20% of ingested alcohol (moderate drinker)
Which ADH isozyme has the highest affinity (lowest Km) for ethanol? Where are they high in quantity?
ADH1 family
high quantity in the liver - why liver is major site of ethanol metabolism
Which isomer of ALDH has highest affinity for acetaldehyde? Where is this enzyme found?
ALDH2
found in the mitochondria
What does inactive ALDH2 cause?
accumulation of acetaldehyde which is toxic to the body - causes flushing, nausea, vomiting and a distaste for alcohol
What causes genetic protection against alcoholism?
AA substitution (Glu -> lys) makes ALDH2*2 which has 23 fold higher Km and 35 fold lower Vmax
*alcoholics are frequently treated with ALDH inhibitors
What is acetate metabolized to?
acetyl CoA by acetyl CoA synthetase (ACS) which is then used in pathways of cholesterol and FA synthesis
What is the most common isoform of ACS in the liver and where is it found?
ACSI found in the cytosol of liver cells
What happens to the majority of acetate?
enters the blood and is taken up by other tissues where it is synthesized by ACS II and can then enter the TCA cycle and be oxidized to CO2
What are the 2 catalytic components of the enzyme used in the MEOS pathway?
- cytochrome P450 reductase (transfers electrons via FAD and FMN from NADPH)
- cytochrome P450 which contains binding sites for O2 and substrate - carries out the reaction
Which cytochrome P450 has the highest activity when ethanol is substrate? What is the Km in comparison to ADH1?
CYP2E1
has a much higher Km for ethanol than ADH1 - so becomes involved when there is a large quantity of ethanol
What are the products of alcohol oxidation by CYP2E1?
acetaldehyde and ROS
which result in oxidative stress and damage
What does chronic consumption of alcohol induce?
expression of CYP2E1 5-10 fold via stabilization of the protein and protection against degradation
What factors determine individual differences in ethanol metabolism?
- genotypes (different polymorphic forms of ADHs and ALDHs)
- drinking history (level of ADH decreases and CYP2E1 increases over time)
- gender (women have lower ADH activity)
- quantity consumed (greater quantity = greater involvement of CYP2E1)
What are the acute effects on liver metabolism due to ethanol consumption?
- inhibition of FA oxidation
- stimulation of TAG synthesis leading to a fatty liver
- ketoacidosis or lactic acidosiswhich cause hypo or hyperglycemia (depending on dietary states)
What effects do actealdehyde and ROS have?
- alcohol induced hepatitis characterized by liver inflammation and necrotic cell death
- damage to hepatocytes leading to cirrhosis characterized by fibrosis, altered blood flow, and loss of liver function
What is the mechanism of acute effects on lipid metabolism in the liver?
- ethanol oxidation by ADH and ALDH increases NADH/NAD+
- high NADH/NAD+ ratio inhibits FA oxidation and the TCA cycle - accumulation of free FA
- FA are reesteried to gylcerol 3-P - increased TAGs are converted to VLDL which accumulate in the liver, enter the blood leading to hepatic steatosis and ethanol induced lipidemia
- FA that are oxidized are converted to acetyl CoA and then to ketone bodies
- inhibition of the TCA cycle causes actyl CoA to enter the ketone body pathway raising their levels (ketoacidosis)
What are the effects of increased NADH/NAD+ due to ethanol oxidation?
- inhibits FA oxidation and the TCA cycle - accumulation of free FA
- increased production of lactate = lactic acidosis (increased lactate decreases uric acid excretion by the kidney)
- shifts the lactate dehydrogenase equilibrium toward production of lactate at the expense of pyruvate
What are the effects of chronic alcohol consumption?
- increased acetaldehyde and ROS in the liver and released into the blood
- acetaldehyde forms adducts with amino and sulfhydryl groups within amino acids and protein and with nucleotides and phospholipids
- accumulation of proteins causes water to enter hepatocytes = swelling = portal hypertension = cell damage = release of AST and ALT
- induction of MEOS = increase ROS production
- peroxidation of lipids in mitochondrial inner membrane and oxidative damage to proteins inhibits electron transport
What does adduct formation as a result of chronic alcohol consumption cause?
- adduct formation with amino acids causes decrease in protein synthesis
- forms adduct with GSH and various antioxidant enzymes (can’t protect against the ROS)
- adduct formation with proteins cause loss of function
What does an insult the the liver, such as chronic alcohol consumption, cause?
a “wound-healing-like reaction”
= overproduction of extracellular matrix which progresses to sclerosis (degeneration of the components of the extracellular matrix)
fibrosis –> cirrhosis
What is hepatic cirrhosis?
when liver damage is irreversible liver function is lost (full of fat and fibrosis and initially enlarged) - starts to become shrunken causes jaundice (toxic levels of ammonia and secretion of bilirubin)
What are alcohol-related diseases?
- obesity (caloric content of ethanol)
- alcoholism (addiction leading to damage of internal organs)
- jaundice (reduced ability of liver to conjugate and solubilize bilirubin = deposition in eyes and skin)
- liver fibrosis (excessive damage to liver)
