lecture 25: alcohol metabolism

Question 1

alcohol absorption

Answer 1

simple diffusion along GI tract
mostly metabolized by liver

Question 2

alcohol dehydrogenase (ADH)

Answer 2

breaking down small quantities of alcohol

Question 3

microsomal ethanol-oxidizing system (MEOS)

Answer 3

important for breaking down large amounts of alcohol, works in addition to ADH

Question 4

ADH system

Answer 4

ADH: ethanol > acetaldehyde
ALDH: acetaldehyde > acetic acid + NADH (inhibits CAC)

Question 5

ALDH (aldehyde dehydrogenase) deficiency

Answer 5

acetaldehyde buildup causing red face

Question 6

MEOS system

Answer 6

metabolizes ethanol to acetaldehyde in alternate pathway
Dependent on CYP2E1/cyt p450: lower affinity for ethanol than ADH
pathway increases after chronic alcohol consumption

consumes O2, may be released prematurely as superoxide

Question 7

superoxide

Answer 7

can be released from MEOS pathway
central role in alcohol induced liver injury
capable of damage and results in production of other oxidative species

formation of hydroxyl radicals

Question 8

if excess alcohol is consumed, NAD to NADH equilibrium…

Answer 8

pushed toward NADH

NADH inhibits CAC
blocks catabolism of acetyl-CoA
accumulation of acetyl-CoA promotes FA synthesis

Question 9

alcohol physical effects

Answer 9

vasodilator: increase blood flow, accelerate hypothermia

antidiuretic, inhibitor of AVP > water loss > accelerates hypothermia

Question 10

nitric oxide (NO) and ethanol

Answer 10

ethanol stimulates production of NO

ethanol produces O2- > increases intracellular Ca2+ >
Ca2+ binds and activates calmodulin > eNOS activation

Question 11

GABA effects

Answer 11

primary inhibitory neurotransmitter in CNS

GABA binding causes opening of ion channels > hyperpolarized membrane > inhibit postsynaptic cell

Question 12

GABA and ethanol

Answer 12

ethanol enhances GABA activity by binding to GABA receptors

greater inhibition of the neuron, relaxing anti-anxiety effects

GABA activity reduced after chronic alcohol exposure and during withdrawal
inhibits ability to synthesize GABA

Question 13

glutamate decarboxylase

Answer 13

synthesizes GABA from glutamate
vitamin B6 = cofactor, decreased vitamin B6 associated with alcoholism

Question 14

Alcoholic Liver Disease (ALD)

Answer 14

spectrum of liver diseases triggered by inflammation

risk increases in a dose and time dependent manner with alc consumption

Question 15

steatosis

Answer 15

abnormal retention of lipids within a cell, often associated in the liver

Question 16

how does over-consumption of alcohol promote lipid accumulation?

Answer 16

1) NAD+/NADH balance
increased NADH > FA synthesis and esterification, decrease B-oxidation

2) Oxygen metabolism
oxidation of ethanol by MEOS consumes oxygen > decrease in cellular O2 > impairs ETC (decreased ATP, increased NADH)
reoxygenation > oxidative stress

Question 17

oxidative stress

Answer 17

overproduction of reactive oxygen and nitrogen species (ROS and RNS)

Question 18

NOX (NADPH oxidase)

Answer 18

membrane bound enzyme activated as a part of immune response
alcohol exposure > NOX activation > increased ROS, oxidative stress

Question 19

enhanced production of TNFa

Answer 19

effect of ethanol

ethanol starts signaling cascade, increases transcription factors (NF-KB, EGR-1) that increase TNFa expression

Question 20

LPS (lipopolysaccharide)

Answer 20

component of cell walls of some bacteria that inhabit intestine
LPS released when bacteria die
ALD > increased LPS in blood > TNFa production

Question 21

TNFa

Answer 21

factor in injury to liver cells
cell signaling protein involved in inflammation
increases with alcohol
increases FA synthesis

Question 22

How does GABA work, and how is its activity being impacted by moderate and chronic alcohol use?

Answer 22

GABA: inhibitory neurotransmitter, binding causes the opening of ion channels, hyperpolarizes the membrane, inhibits the postsynaptic cell
Ethanol binds directly to GABA receptors
Moderate: enhances GABA activity, anti-anxiety effect
Chronic: reduced GABA activity due to decreased vitamin B6 (cofactor in GABA synthesis), reduced inhibitory effects

Question 23

What does LPS have to do with alcoholism? LPS and ethanol can lead to the increased expression of what cytokine? What is this cytokine involved in, and why is it over expression problematic?

Answer 23

LPS is in bacteria that inhabit the intestine
Chronic alcoholism increases intestinal permeability > LPS in bloodstream

LPS causes overexpression of TNFa: chronic inflammation > diseases

Question 24

How does the consumption of excess alcohol promote fat synthesis?

Answer 24

Alcohol dehydrogenase: ADH in ethanol metabolism causes shift toward NADH in NADH/NAD ratio > CAC inhibited > acetyl-CoA accumulation > acetyl CoA to FA oxidation, B-oxidation is decreased

MEOS: pathway with large amounts of alcohol, consumes O2 > slows ETC, slows NADH oxidation (increases NADH)