Alcohol metabolism 21 Flashcards
Is ethanol water soluble or lipid soluble?
both
Where is most ethanol metabolized
the liver
What are the two steps of alcohol oxidation in the liver using ADH and ALDH?
- ADH in cytosol
ethanol –> acetaldehyde - ALDH in mitochondria
acetaldehyde –> acetate
Both produce NADH
What is the highest affinity (lowest Km) ADH? where is it found?
ADH1
liver
Where is ADH4 found?
upper GI tract
Where is ADH2 found?
liver and lower GI tract
Where is ADH3 found and what is it active towards?
many tissues
inactive towards ethanol
active towards long chain alcohols
What is the major ALDH ?
ALDH2 in the liver (mitochondrial)
where in the cell is ALDH1 found?
cytoplasm
What are the symptoms of inactive ALDH2? what substitution causes this?
flushing, nausea, vomiting, distaste for alcohol
-GLU to LYS at residue 487
What does acetyl coA synthetase convert?
acetate –> acetyl coA
What is the primary isoform of acetyl coA synthetase in liver? What part of the cell is it found in?
ACS1 (cytosolic)
What acetyl coA synthetase isoform is in the mitochondria of heart and skeletal muscle?
ACSII
What happens to the acetyl coA generated by ACS?
enters the TCA cycle and is oxidized to CO2
What is a second pathway for the breakdown of ethanol besides ADH and ALDH?
MEOS in the liver - ER cytochrome P450s
What are the two components of MEOS?
- cytochrome P450 reductase
- transfers e- via FAD and FMN from NADPH - Cytochrome P450
contains binding sites for O2 and ethanol
carries out the reaction to acetaldehyde
Does ADH1 or CYP2E1 have a higher affinity for ethanol?
ADH1
cyp2E1 more involved with large quantities
What products are produced by the oxidation of ethanol by CYP2E1?
acetaldehyde and ROS
Is CYP2E1 expression affected by alcohol consumption?
yes chronic consumption increases expression 5-10 fold
-ethanol stabilizes the protein
What are four types of variations that determine how well ethanol is metabolized in a person?
- genotype
- drinking history
- gender
- quantity
How are a heavy drinkers ADH and CYP2E1 levels affected?
ADH dec
CYP2E1 increases
Women have less of what enzyme than men?
gastric ADH
Acute effects of alcohol damage are all a result of what?
increased NADH/NAD+ ratio
What two metabolic processes does a high NADH/NAD+ ratio inhibit?
FA oxidation
TCA cycle
What reesterifies fatty acids to G3P in the ER, due to a high NADH/NAD+ ratio?
acyl transferases
What results from accumulation of VLDL in the liver?
fatty liver - hepatic steatosis
ethanol induced lipidemia
Since TCA cycle is inhibited by NADH/NAD+, what are fatty acids converted to?
ketone bodies
Why are patients with gout advised not to drink?
increase of blood lactate decreases uric acid excretion in the kidney
alcohol in the fasting state can cause? alcohol with a meal causes?
fasting state: hypoglycemia
with a meal: transient hyperglycemia
What specifically causes the chronic, irreversible effects of alcohol consumption?
acetylaldehyde adducts
ROS species
Acetylaldehyde formation with AAs causes what?
decrease protein synthesis
What antioxidant enzyme does acetyladehdye specifically adduct to?
GSH
What is the effect of the peroxidation of lipids in the mitochondrial membrane?
inhibits electron transport
Adduct formation with tubulin affects what?
protein secretion
accumulation of proteins causes what effect?
water to enter hepatocytes
portal hypertension
cell damage - release of AST, ALT
What is fibrosis?
a wound healing like reaction
overproduction of ECM
capillary formation in sinusoids
What percentage of heavy drinkers progress from fibrosis to cirrhosis?
20%
Is cirrhosis reversible?
nah dude you’re screwed
what causes jaundice?
diminished ability of the liver to conjugate and secrete bilirubin
What are four alcohol related diseases?
- obesity
- alcoholism
- jaundice
- liver fibrosis
