Alcohol metabolism

Question 1

What two enzymes metabolize alcohol?

Answer 1

Alcohol dehydrogenase and aldehyde dehydrogenase

Or

CYP2E1

Question 2

Where is CYP2E1 enzyme located?

Answer 2

In the ER

Question 3

Where is alcohol dehydrogenase located?

Answer 3

Cytosol

Question 4

Where is aldehyde dehydrogenase located?

Answer 4

Mitochondria

Question 5

Which of the enzymes in alcohol metabolism are inducible?

Answer 5

CYP2E1 is highly inducible by ethanol

Question 6

Which ezyme in alcohol metabolism is high affinity?

which is low affinity?

Answer 6

Alcohol dehydrogenase is high affinity and non-inducible

CYP2E1 is low affinity and highly inducible

Question 7

What is ethanol generated from in yeast fermentation?

Answer 7

Pyruvate –> Acetaldehyde –> Ethanol

It allows they to survive anaerobic conditions, and provides ethanol as a weak antimicrobial.

Question 8

How is alcohol metabolized differently in men and women and in a fed or fasted state

Answer 8

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.

Question 9

What is responsible for the toxic effects of alcohol metabolised by alcohol dehydrogenase?

Answer 9

acetaldehyde buildup

Question 10

What are the toxins built up when alcohol is metabolized by CYP2E1

Answer 10

Reactive oxygen species, as well as acetaldehyde.

Question 11

How does ethanol increase CYP2E1 levels.

Answer 11

It induces its expression and also prolongs its half life, by inhibiting ubiquitination of CYP2E1

Question 12

How does alcohol dehydrogenase affect the redox balance?

Answer 12

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.

Question 13

How does CYP2E1 ethanol metabolism affect the redox balance?

Answer 13

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.

Question 14

How is acetaldehyde toxic?

Answer 14

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.

Question 15

How does alcohol negatively affect the GI tract?

Answer 15

It can increase intestinal permeability
and
Inhibit Reticuloendothelial cell system activity,
Increasing infections and sepsis.

Question 16

How does low does vs. chronic or medium/high does alcohol affect the cardiovascular system?

Answer 16

Low dose
Increases HDL levels, 
Decreases oxidized LDL levels. 
Reduces platelet aggregation 
Increases fibrinolysis
Reduces stress

medium or high dose
Increases risk of:
Hypertension
Ischemic heart disease
Coronary heart disease
Ischemic or hemorrhagic stroke.

Question 17

What are possible consequences of strong CYP2E1 induction?

Answer 17

hypoxia (uses O2 as the e acceptor)

oxidative stress, ROS generation

acetaldehyde accumulation

accumulation of drug intermediates and altered drug metabolism.

carcinogenesis over long periods

alteration in testosterone metabolism

Question 18

What random intracellular signaling pathways does chronic alcoholism affect?

Answer 18

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.

Question 19

What major drug does CYP2E1 metabolize?

Answer 19

PARACETAMOL
aka
Acetaminophen.

Question 20

How is acetaminophen metabolism different in normal vs. alcoholics?

Answer 20

Paracetamol/acetominophen is normally metabolized without toxic intermediates.

In an alcoholic condition, CYP2E1 is induced highly, and metabolism of paracetamol by CYP2E1 produces the highly toxic NAPQI.
N acetyl p benzoquinonimine, NAPQI.

Its downstream metabolites also generate other ROS.

So an alcoholic who takes acetominophen at a time when they have not consumed any alcohol will have it almost all converted by this toxic intermediate generating pathway and are at risk for acute liver toxicity.