Ethanol Metabolism - Abali 3/10/16 Flashcards
mechanisms involved with acute ethanol tox
ethanol → acetyl CoA → moves into…
- ADH system : robust
- MEOS system : accesory system
- brain fx depressant
- acetyl CoA doesn’t have anywhere to go, so enters FA synth → alcoholic fatty liver disease
- acetaldehyde forms adducts with proteins and nucleic acids
- increased NADH/NAD+ → increases lactate/pyruvate ratio, inhibits gluconeogenesis, inhibits FA beta ox (tricks body into thinking it’s in a high energy state!)
alcohol absorption
no digestion required!
absorbed in:
- mouth, esophagus (minor players)
- stomach (readily abs, but inhibited by food)
- sm int (primary site)
presence of food slows abs and also prevents the sharp peak in BAC
alcohol elimination
5% breath
5% urine
90% broken down by liver enzymes
systems of ethanol metabolism
3 enzyme systems responsible for ethanol metabolism:
-
ADH: cytosolic alcohol dehydrogenase (enterocytes, to a certain extent)
* main mech, v robust - MEOS: microsomal ethanol oxidation system (smooth ER)
- deals with “overflow” in high alcohol consumption
- has interactions with some drugs
-
catalase in peroxisomes
product: acetaldehyde, transported to mitochondria for further metab → acetate
metabolizing small to moderate amounts of alcohol
how NADH accumulates
two rxns, both take NAD+ → NADH
- alcohol → acetaldehyde [alcohol DH; 1 NADH made]
- acetaldehyde + CoA → acetyl CoA [acetaldehyde DH; 1 NADH made]
net: alcohol consumed; acetyl CoA + 2 NADH made
metabolizing small to moderate amounts of alcohol
effect of NADH accumulation
net: alcohol consumed; acetyl CoA + 2 NADH made
1. energy depletion
- pyruvate DH inhibited (false “high energy” state) → lactic acidosis
- TCA cycle inhibited
2. hypoglycemia
- gluconeogenesis inhibited
- glycolysis inhibited
3. acetyl CoA buildup shunted into other pathways
- FA synthesis increases
- ketone body synthesis increases → ketoacidosis
alcohol and inhibition of glycolysis
how does this lead to lactic acidosis and ketoacidosis?
PDH shut down
PDH requires NAD+, is allosterically regulated by NADH → pyruvate moves either to lactate (lactic acidosis) or backwards to glyceraldehyde3P
- glyceraldehyde3P can be converted to glycerol3P → FA synth!
NADH buildup → body senses “high egy” → FA degradation inhibited
acetyl CoA buildup, NADH buildup → hydroxybutyrate
how does alcohol inhibit the TCA cycle and gluconeogenesis?
accumulation of high egy mols (NADH) leads to reversal of some rxns in TCA cycle: OAA → malate
- accumulation of malate and high egy mols leads to inhibition of TCA cycle
also shuts down pyruvate carboxylase (pyruvate → OAA)
- inhibits gluconeogenesis (for which OAA is an imp precursor)
hyperuricemic effect of alcohol
urate reabsorption transport through URAT1 is triggered by lactic acidosis and ketoacidosis during heavy alcohol use
URAT1: trades organic anions (lactate, ketone bodies, etc) out for urate in
metabolic effects of ethanol: summary
- NADH blocks conversion of malate → OAA, gluconeogenesis blocked
- glyceraldehyde3P DH runs backwards due to high NADH → glycolysis blocked
- conversion of lactate back to pyruvate by lactate DH is blocked by high NADH → lactic acidosis
overall, intoxication can lead to hypoglycemia and lactic acidosis
might also cause irreversible CNS damage
why do you feel warmer when drinking?
acetaldehyde is a peripheral vasodilator - enlarges vessels near the skin, causing you to feel warmer
genetic influences : protection against devpt of alcoholism
alcohol→acetaldehyde [ADH]→acetone [ALDH]
acetaldehyde buildup causes negative symptoms: flushing, headache, nausea, etc
more likely when…
- high ADH activity, low ALDH → acetaldehyde buildup
- low ALDH → acetaldehyde buildup
the lousy symptoms make it less likely that you’ll develop a habit
genetic influences : propensity for devpt of alcoholism
acetaldehyde buildup causes negative symptoms: flushing, headache, nausea, etc
less likely when…
- low ADH activity, high ALDH → acetaldehyde cleared, acetate buildup
- high ALDH → acetaldehyde clearance, acetate buildup
you never feel the lousy side effects, and so you develop a habit quicker
disulfiram
anti-alcohol abuse med
deactivates ALDH → causes acetaldehyde buildup, along with the negative side effects!
- response to even small amt of alcohol, starting after 10 min, lasting for an hour or more
- discourages drinking
MEOS
- when is it activated
- how does it work
microsomal ethanol oxidizing system
- in excess alcohol consumption, ADH system can be overwhelmed → overflow handled by MEOS system
makes use of CYP2E1 to get alcohol → acetaldehyde
- can be activated by chronic alcohol use
- interacts with mech of action of many drugs
- acetominiphen
- isoniazid (TB drug)
- phenobarbital
role of CYP2E1 in alcohol-medication interactions
- normal
- moderal alc consumption
- chronic alc consumption; sober
- chronic alc consumption; drinking
normal
drug is metabolized by cyp, excreted
moderate alc consumption
alcohol competes with drug for binding to cyp → less drug metabolized; some can interact with CNS
chronic alc consumption; sober
have more cyp on hand, metabolize more of the drug → drug metabolite toxicity!!!
chronic alc consumption; drinking
alcohol competes with drug for binding to cyp → less drug metabolized; some can interact with CN
alcohol-acetominophen interaction
normally…
acetominophen → NAPQ1 (toxic intermed) → detox’d, excreted
in chronic drinkers (who are sobers), you have a greater stock of activated cyp, which means…
greater production of NAPQ1 → can’t be detox’d and excreted as efficiently → liver toxicity
tx: n-acetylCys: increases glutathione synthesis to get rid of toxic intermed!
effect of alcohol abuse on nutritional status
- kwashiorkor
- mineral deficiencies
* Ca, Fe, Zn, Mg - vitamin deficiencies
alcohol and water soluble vitamins
- effect: interference with absorption
- liver is storage site for folate, B12: disruption of liver → folate/B12 def → messes with rapidly dividing gut epithelial cells → messes with abs
- acetaldehyde disrupts the protein that binds thiamine → body can’t hold onto B1 → Wernicke Korsakoff!!!
- effect: increased excretion
* greater loss of pyridoxine B6 → messes with PLP, protein metabolism - demand: need more niacin for alc metabolism!!!
* NAD+ is critical for metabolizing alc
alcohol and fat soluble vitamins
A: can’t be converted from retinol → retinyl ester
- night blindness
D: affects 25 hydroxylation of vit D bc liver is damaged
- osteoporosis
K: chances are bacteria are messed up as well
- formation of prothrombin, clotting factors affected → bleeding problems
alcohol and pregnancy
can mess with energy production (via pyruvate DH especially) needed to support fetus
fetal alcohol syndrome
- growth retardation starting before, continuing after birth
- impairment of CNS (mental retardation, motor abnormality, tremor, hyperactivity)
- similar to PDH deficiency (just in this case, PDH is inhibited by NADH buildup)
