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Scientific Foundations > Lecture 51 > Flashcards

Lecture 51 Flashcards

Alcohol Metabolism and Metabolic Effects of Alcohol Excess

1
Q

ethanol as energy source

A
  • ethanol is 4th major “nutient”
  • provides “empty calories” -> but a LOT of them
  • a “standard drink” has about 14 grams of ethanol -> ~100 kcal/drink (ONLY from the alcohol)
  • ethanol is only alcohol that can be consumed without any immediate toxic effects

pg 1323

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2
Q

liver role in ethanol metabolism

A
  • ethanol = alcohol, broken down to NADH
  • ethanol is a small molecule which is soluble in both organic solvents and water, can easily cross membranes
  • ethanol enters liver hepatocytes from blood stream and is metabolized by 2 different systems in the liver
  • 80-90% of ethanol broken down to acetaldehyde by alcohol dehydrogenase

pg 1324

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3
Q

alcohol dehydrogenase (ADH)

A
  • metabolizes 80-90% of the ethanol in liver cells (predominantly)
  • rate-limiting step
  • only limiting factor is availability of NAD+
  • converts ethanol to acetaldehyde and produces NADH (electron transfer to transport to ETC)

pg 1325

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4
Q

kinetics of ADH

A
  • Km of liver ADH (ADH1) is nearly 1 mmol/L (46 mg/L) -> the enzyme is essentially saturated after only one drink -> with a second drink, ethanol remains in circulation because it takes time for it be released from ADH
  • ethanol metabolism follows zero-order kinetics
  • most people metabolize ~10 g of alcohol per hour, and the blood alcohol level decreases by about 0.15 g/L every hour

pg 1325

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5
Q

genetics of ADH

A
  • exists as a family of at least 6 isoenzymes with varying specificity for chain length of the alcohol substrate
  • known polymorphism that reflects on individual experiences (aka different alcohol tolerance based on speed of metabolism)

pg 1325

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6
Q

liver role in ethanol metabolism pt 2

A

other method of ethanol metabolism in the liver is MEOS (ER microsomal ethanol-oxidizing system) which is responsible for 10-20% of ethanol conversion to acetaldehyde

pg 1326

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7
Q

ER microsomal ethanol-oxidizing system (MEOS)

A
  • metabolizes only 10-20% in moderate drinking (Km for ethanol is much higher than ADH) → uses cytochrome p450 enzymes
  • requires oxygen and NADPH (from PPP) for conversion to acetaldehyde
  • induced at transcriptional, post-transcriptional, and post-translational level in heavy drinkers
  • induction potentiates toxicity of acetaminophen

pg 1327

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8
Q

liver role in ethanol metabolism pt 3

A
  • ethanol can be converted to acetaldehyde by catalase in the brain -> accounts for less than 2% of metabolism
  • catalase has no role in the liver and is rarely used

pg 1328

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9
Q

acetaldehyde

A
  • very toxic
  • accounts for most of the physical damage in chronic alcohol use
  • symptoms of acetaldehyde toxicity include flushing of the face and nausea

pg 1329

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10
Q

chronic alcohol use and liver disease

A

developments of hepatic fibrosis: proposed model

  • acetaldehyde contributes to chronic disease in alcohol use disorder
  • acetaldehyde accumulation is toxic
  • acetaldehyde activates Kupffer cells (resident macrophages)
  • activated Kupffer cells release TGF-β which activates stellate cells (vitamin A)
  • stimulated stellate cells produce ECM, collagen, metallo, and proteases -> this leads to fibrosis
  • toxicity comes from acetaldehyde in chronic alcohol use

pg 1330, 1339

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11
Q

liver role in ethanol metabolism pt 4

A

in mitochondria, acetaldehyde is broken down into acetate by ALDH

pg 1331

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12
Q

aldehyde dehydrogenase (ALDH)

A
  • two enzymes with different locations
  • mitochondrial ALDH (ALDH2) -> high affinity and specificity
  • cytosolic ALDH (ALDH1) -> may act on a variety of organic alcohols, toxins, and pollutants
  • converts acetaldehyde to acetate

pg 1332

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13
Q

ALDH genetics

A
  • polymorphism in ALDH2 in 30-40% of East Asians having an atypical ALDH with a single amino acid substitution (Glu->Lys, dominant negative) -> inefficient ALDH function
  • results in oriental flush response, with vasodilation, facial flushing, and tachycardia
  • provides a natural “protection” from alcoholism

pg 1332

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14
Q

ALDH inhibition

A
  • disulfiram (antabuse) → inhibitor of ALDH to cause oriental flush response (unpleasant reaction leading to alcohol avoidance)
  • results in acetaldehyde accumulation

pg 1332

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15
Q

liver role in ethanol metabolism pt 6

A

acetate converted to acetyl CoA by acetyl CoA synthetase (requires ATP)

pg 1333

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16
Q

acetyl CoA synthetase I (ACSI)

A
  • a cytosolic enzyme that generates acetyl CoA for the cytosolic pathways of cholesterol and fatty acid synthesis
  • acetate entry into these pathways is under the strict regulatory control by mechanisms involving cholesterol or insulin
  • most of the acetate generated enters the blood
  • converts acetate to acetyl CoA

pg 1334

17
Q

liver role in ethanol metabolism pt 7

A
  • acetate can be released to blood to provide energy to muscles
  • acetyl CoA converted to FAs and released in VLDL to the blood
  • excess acetyl CoA converted to ketone bodies which are then released to the blood stream

pg 1335

18
Q

metabolic effects of acute alcohol use

A
  • NO regulation for ethanol metabolism so NADH accumulates -> NADH allosteric regulator for many pathways leading to the following effects:
  • hypoglycemia (in fasted state) -> liver cannot activate GNG (pyruvate to lactate uses NADH)
  • transient hyperglycemia (in well-fed state)
  • lactic acidosis
  • hyperuricemia
  • ketoacidosis
  • hyperlipidemia
  • fatty liver (ALD)

pg 1337-1338

19
Q

hepatic steatosis/fatty liver

A
  • caused by aging, alcoholism, certain drugs, obesity, overnutrition (poor diet), and sedentary lifestyle
  • reversible by lifestyle changes -> liver can go back to normal with proper changes
  • MAFLD and AFLD are fatty liver (metabolic alcoholic fatty liver disease)
  • a risk factor for: insulin resistance, diabetes, atherosclerosis, cardiovascular diseases
  • in alcohol use disorder, steatosis/fatty liver leads to steatohepatitis and eventually cirrhosis (end stage liver disease)

pg 1340

20
Q

malnutrition in alcohol use disorder

A
  • significant amount of the daily caloric intake comes from ethanol
  • all negative effects on the liver, pancreas, and GI tract further increase nutritional malabsorption
  • two vitamin deficiencies are particularly prevalent in patients with alcohol use disorder:
  • folate deficiency is often seen, which results in megaloblastic anemia
  • thiamine deficiency due to chronic alcohol use causes Wernicke-Korsakoff syndrome

pg 1341

21
Q

Wernicke’s encephalopathy

A
  • symptoms: confusion, tremors, ataxia (loss of coordination), nystagmus, and other vision problems
  • at this stage, the damage is not permanent and can be reversed by thiamine supplementation
  • usually, in hospital admissions, thiamine is injected to assure delivery (the intestinal damage in alcoholics interferes with absorption)
  • damage is largely reversible

pg 1342

22
Q

Korsakoff syndrome

A
  • as the Wernicke’s stage progresses, eventually the symptoms of Korsakoff syndrome will develop
  • this will include memory loss and inability to form new memories, confabulation, hallucinations, and delerium
  • damage at this stage is usually irreversible and brain damage is permanent

pg 1342

23
Q

alcohol consumption and pregnancy

A
  • during pregnancy, estrogen levels largely inhibit the activity of ADH
  • alcohol in the blood of the mother moves to the blood of the fetus
  • ability of the fetus to metabolize alcohol is suppressed (ADH is not expressed yet) (ADH detectable at 2 months gestation but only at 5-10% activity)
  • alcohol remains longer in the blood and interferes with the ability of the fetus to use oxygen and develop normally
  • exposure during the first trimester can be especially harmful

pg 1343

24
Q

fetal alcohol spectrum disorder (FASD)

A
  • any physical or developmental disorders caused by prenatal alcohol exposure
  • estimated to be 2-5% of population
  • changes depend on the amount, frequency, and the timing of the consumption of alcohol by the mother during pregnancy

pg 1343

25
Q

methanol (CH3OH)

A
  • formed in very small amounts during fermentation
  • potential hazard in home distillation of alcohol
  • metabolized in the liver by ADH and ALDH
  • methanol -> formic acid -> formaldehyde

pg 1344

26
Q

ethylene glycol

A
  • found in automotive antifreeze or radiator coolants
  • colorless, odorless sweet liquid -> attractive for children
  • metabolized in the liver by ADH and ALDH
  • ethylene glycol -> glycol aldehyde -> glycolic acid
  • VERY toxic

pg 1345

27
Q

treatment for methanol and ethylene glycol toxicity

A
  • administration of antidotes
  • fomepizole (IV) -> competitive inhibitor of the ADH enzyme (used in ER)
  • ethanol -> competes with methanol/ethylene glycol for ADH; ADH has 100x greater affinity for ethanol so successfully blocks their breakdown into toxic compounds

pg 1346

Scientific Foundations (46 decks)

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