lecture 25: alcohol metabolism Flashcards
alcohol absorption
simple diffusion along GI tract
mostly metabolized by liver
alcohol dehydrogenase (ADH)
breaking down small quantities of alcohol
microsomal ethanol-oxidizing system (MEOS)
important for breaking down large amounts of alcohol, works in addition to ADH
ADH system
ADH: ethanol > acetaldehyde
ALDH: acetaldehyde > acetic acid + NADH (inhibits CAC)
ALDH (aldehyde dehydrogenase) deficiency
acetaldehyde buildup causing red face
MEOS system
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
superoxide
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
if excess alcohol is consumed, NAD to NADH equilibrium…
pushed toward NADH
NADH inhibits CAC
blocks catabolism of acetyl-CoA
accumulation of acetyl-CoA promotes FA synthesis
alcohol physical effects
vasodilator: increase blood flow, accelerate hypothermia
antidiuretic, inhibitor of AVP > water loss > accelerates hypothermia
nitric oxide (NO) and ethanol
ethanol stimulates production of NO
ethanol produces O2- > increases intracellular Ca2+ >
Ca2+ binds and activates calmodulin > eNOS activation
GABA effects
primary inhibitory neurotransmitter in CNS
GABA binding causes opening of ion channels > hyperpolarized membrane > inhibit postsynaptic cell
GABA and ethanol
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
glutamate decarboxylase
synthesizes GABA from glutamate
vitamin B6 = cofactor, decreased vitamin B6 associated with alcoholism
Alcoholic Liver Disease (ALD)
spectrum of liver diseases triggered by inflammation
risk increases in a dose and time dependent manner with alc consumption
steatosis
abnormal retention of lipids within a cell, often associated in the liver
how does over-consumption of alcohol promote lipid accumulation?
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
oxidative stress
overproduction of reactive oxygen and nitrogen species (ROS and RNS)
NOX (NADPH oxidase)
membrane bound enzyme activated as a part of immune response
alcohol exposure > NOX activation > increased ROS, oxidative stress
enhanced production of TNFa
effect of ethanol
ethanol starts signaling cascade, increases transcription factors (NF-KB, EGR-1) that increase TNFa expression
LPS (lipopolysaccharide)
component of cell walls of some bacteria that inhabit intestine
LPS released when bacteria die
ALD > increased LPS in blood > TNFa production
TNFa
factor in injury to liver cells
cell signaling protein involved in inflammation
increases with alcohol
increases FA synthesis
How does GABA work, and how is its activity being impacted by moderate and chronic alcohol use?
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
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?
LPS is in bacteria that inhabit the intestine
Chronic alcoholism increases intestinal permeability > LPS in bloodstream
LPS causes overexpression of TNFa: chronic inflammation > diseases
How does the consumption of excess alcohol promote fat synthesis?
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)
