Ethanol Metabolism - Abali 3/10/16 Flashcards Preview

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Flashcards in Ethanol Metabolism - Abali 3/10/16 Deck (21):
1

mechanisms involved with acute ethanol tox

ethanol → acetyl CoA → moves into...

1. ADH system : robust

2. 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!)

2

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

3

alcohol elimination

5% breath

5% urine

90% broken down by liver enzymes

4

systems of ethanol metabolism

3 enzyme systems responsible for ethanol metabolism:

1. ADHcytosolic alcohol dehydrogenase (enterocytes, to a certain extent)

  • main mech, v robust

2. MEOSmicrosomal ethanol oxidation system (smooth ER)

  • deals with "overflow" in high alcohol consumption
  • has interactions with some drugs

3. catalase in peroxisomes 

 

product: acetaldehyde, transported to mitochondria for further metab → acetate

5

metabolizing small to moderate amounts of alcohol

 

how NADH accumulates

two rxns, both take NAD+ → NADH

1. alcohol → acetaldehyde [alcohol DH; 1 NADH made]

2. acetaldehyde + CoA → acetyl CoA [acetaldehyde DH; 1 NADH made]

net: alcohol consumed; acetyl CoA + 2 NADH made

6

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

7

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

8

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)

9

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

10

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

11

why do you feel warmer when drinking?

acetaldehyde is a peripheral vasodilator - enlarges vessels near the skin, causing you to feel warmer

12

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

13

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

14

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

15

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

16

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

17

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!

18

effect of alcohol abuse on nutritional status

1. kwashiorkor

2. mineral deficiencies 

  • Ca, Fe, Zn, Mg

3. vitamin deficiencies

19

alcohol and water soluble vitamins

1. 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!!!

2. effect: increased excretion

  • greater loss of pyridoxine B6 → messes with PLP, protein metabolism

3. demand: need more niacin for alc metabolism!!!

  • NAD+ is critical for metabolizing alc

20

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

21

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)