Liver Metabolism 7: Detoxification And Alcohol Metabolism Flashcards

1
Q

Review of how many kcal/g is found in the 3 main macronutrients and alcohol?

A

Carbohydrates = 4 kcal/g

Protein = 4 kcal/g

Fat = 9 kcal/g

Alcohol = 7 kcal/g

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2
Q

How does the liver break down ethanol?

A

Goes through one of two pathways

1) alcohol dehydrogenase (80-90%)
2) Microsomal Ethanol-Oxidizing System (MEOS) pathway (10-20%)

  • *both pathways produce acetaldehyde-> acetate**
  • acetate is either sent to muscles for fuel or converted into acetyl CoA and then either
    1) ketone bodies in the liver
    2) Palmitate cholesterol
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3
Q

How does the MEOS system work?

A

only metabolizes up to 20% of a moderate drink and has a high Km for ethanol (requires quite alot to be saturated)

Is induced at transcriptional posttranscriptional and posttranslational level in heavy drinkers
- ** induction potentiates toxicity of acetaminophen

Takes ethanol in the ER and converts it to acetaldehyde in the cytosol

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4
Q

What CYP protein has the highest affinity for ethanol?

A

CYP2E1

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5
Q

What is the primary enzyme and rate limiting step of ethanol metabolism?

A
Alcohol dehydrogenase (ADH)
- *requires NAD+ to be available since this is the limiting factor* 

Two types:

  • ALDH2 = mitochondrial type
  • ALDH1 = cytosolic type

Metabolizes 80-90% of the ethanol in liver cells

Lower Km than MEOS system (so saturates really fast)

  • *ethanol metabolism follows zero-order kinetics**
  • most people metabolize 10g of alcohol per hour
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6
Q

What is the physiological effects of acetaldehyde?

A

It’s a very toxic component that in excess accounts for most of the physician damage in chronic alcoholics

Symptoms:

  • flushing
  • nausea/vomiting
  • “being drunk” symptoms
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7
Q

Aldehyde dehydrogenase (ALDH)

A

Two subtypes:

  • mitochondrial ALDH2
  • cytosolic ALDH1

some eastern Asian populations have polymorphism in ALDH2 genes (30-40%) which results in a dominant negative phenotype. This results in “oriental flush” in response to drinking alcohol (vasodilation/facial flushing and tachycardia)

The purpose of this enzyme is to provide natural “protection” from alcoholism

ALDH inhibition = Disulfiram (Antabuse)

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8
Q

What are the metabolic effects of alcohol abuse?

A

Hypoglycemia (in fasted state)

Transient hyperglycemia (in fed state)

Lactic acidosis

Hyperuricemia

Ketoacidosis

Hyperlipidemia and fatty liver disease

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9
Q

What is the proposed model behind liver fibrosis in chronic alcoholics?

A

Acetaldehyde is consumed in excess by kupffer cells in liver tissue which produces activated kupffer cells

Activated kupffer cells release TGF-B and respiratory bursts/ROS which casues stellate cells to be activated in response

Activated stellate cells produce MMPs and extracellular matrix collagen = fibrosis

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10
Q

What two vitamin deficiencies are most common among alcoholics?

A

Folate = megaloblastic anemia

Thiamine = wernicke-korsakoff syndrome

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11
Q

Why is drinking during pregnancy so dangerous?

A

High levels of estrogen seen in pregnancy inhibits Alcohol dehydrogenase enzymes (ADH)

This causes mass ethanol to remain in the blood which cross the placenta easily
- fetus has NO ADH, so metabolism occurs = toxic and fetal alcohol spectrum disorder

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12
Q

What are the heath benefits from moderate-mild alcohol drinking

A

Helps limit the following:

  • coronary heart disease
  • gallstones
  • strokes
  • diabetes
  • osteoporosis
  • *however increases risks of**
  • cancers
  • injury/fibrosis
  • hemorrhagic stroke
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13
Q

How to treat both methanol and ethylene glycol poisoning

A

IV fomepizole = competitive inhibitor of ADH

can also give ethanol for both since it also competitively binds to ADH

*** the reason both of these work is methanol and ethylene glycol ARE NOT toxic until they are metabolized. If not metabolized, will be eliminated from the body

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14
Q

What are the effects of DEAK vitamin deficiencies and toxicity

A

Vitamin A:

  • deficiency = night blindness and xerophthalmia (dryness of eye which causes keratin synthesis and blindness eventually)
  • toxicity = dry skin, liver cirrhosis, fragile bones, teratogenic in pregnant women

Vitamin D:

  • deficiency = osterodystrophy and osteomalacia/rickets
  • toxicity = hypercalcemia and kidney stones

Vitamin K:

  • deficency = casues unusual bacterial growth and spontaneous bleeding
  • toxicity = NOT POSSIBLE
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15
Q

What does Km and Vmax stand for?

A

Km = affinity for substrate

  • high Km = low affinity for substrate
  • low kM = high affinity for substrate

Vmax = how fast an enzyme metabolizes it’s substrates
- high Vmax = works fast and metabolizes fast

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16
Q

Hemochromatosis and Wilson’s disease

A

Wilson’s disease = excess copper

Hemochromatosis = excess iron