Flashcards in Alcohol metabolism Deck (20)
What two enzymes metabolize alcohol?
Alcohol dehydrogenase and aldehyde dehydrogenase
Where is CYP2E1 enzyme located?
In the ER
Where is alcohol dehydrogenase located?
Where is aldehyde dehydrogenase located?
Which of the enzymes in alcohol metabolism are inducible?
CYP2E1 is highly inducible by ethanol
Which ezyme in alcohol metabolism is high affinity?
which is low affinity?
Alcohol dehydrogenase is high affinity and non-inducible
CYP2E1 is low affinity and highly inducible
What is ethanol generated from in yeast fermentation?
Pyruvate --> Acetaldehyde --> Ethanol
It allows they to survive anaerobic conditions, and provides ethanol as a weak antimicrobial.
How is alcohol metabolized differently in men and women and in a fed or fasted state
Women eleminate alcohol at about 2/3 the rate of men
Fasted state is also about 2/3 the rate of elemination in a fed state. High fat and high protein meals make it elmiinate the fastest.
What is responsible for the toxic effects of alcohol metabolised by alcohol dehydrogenase?
What are the toxins built up when alcohol is metabolized by CYP2E1
Reactive oxygen species, as well as acetaldehyde.
How does ethanol increase CYP2E1 levels.
It induces its expression and also prolongs its half life, by inhibiting ubiquitination of CYP2E1
How does alcohol dehydrogenase affect the redox balance?
Ethanol metabolism by alcohol dehydrogenase produces NADH.
Produces high NADH/NAD+ levels most specifically IN THE LIVER.
decreased beta oxidation and FA degradation
decreased citrate cycle, Acetyl-CoA accumulation, Increased FA synthesis
increased Glycerol 3 phosphate, Increased FA synthesis
TCA cycle inhibited, but need to regenerate NAD+, so LDH is activated and Lactic acidosis occures.
Gluconeogenesis is inhibited, hypoblycemia.
How does CYP2E1 ethanol metabolism affect the redox balance?
CYP2E1 doesn't use NAD/NADH
It uses O2 as the electron acceptor instead of NAD+, and Consumes NADPH + H and O2, to generate two H2O.
It is by this process that it can generate ROS during incomplete oxidation.
How is acetaldehyde toxic?
Mainly by Adduct formation, with virtually any kind of molecule in the cell.
DNA, and DNA repair enzymes -> DNA mutations
GSH and antioxidant enzymes, -> more oxidative damage and DNA mutations
Apolipoproteins --> decreased VLDL production
Tubulin --> Decreased VLDL secretions
These changes are the major causes of cancer and fatty liver.
How does alcohol negatively affect the GI tract?
It can increase intestinal permeability
Inhibit Reticuloendothelial cell system activity,
Increasing infections and sepsis.
How does low does vs. chronic or medium/high does alcohol affect the cardiovascular system?
Increases HDL levels,
Decreases oxidized LDL levels.
Reduces platelet aggregation
medium or high dose
Increases risk of:
Ischemic heart disease
Coronary heart disease
Ischemic or hemorrhagic stroke.
What are possible consequences of strong CYP2E1 induction?
hypoxia (uses O2 as the e acceptor)
oxidative stress, ROS generation
accumulation of drug intermediates and altered drug metabolism.
carcinogenesis over long periods
alteration in testosterone metabolism
What random intracellular signaling pathways does chronic alcoholism affect?
Oxidative stress increases JNK and c-Fos, c-Jun signaling. Increases Cyclin D1, pro-mitotic in hepatocytes
CYP induction decreases Retinoic acid, decreasing RAR/RXR levels, decreasing apoptotic signals.
Overall, increased cyclinD1 and decreases apoptosis, carcinogenic.
What major drug does CYP2E1 metabolize?