Biochem post-midterm- mitochondrial function and hepatic detox of monoamines, alcohol, toluene, heme

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Biochem post-midterm- mitochondrial function and hepatic detox of monoamines, alcohol, toluene, heme
2013-12-15 18:59:47

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  1. MAO-A vs MAO-B
    • A preferentially metabolizes serotonin
    • B preferentially metabolizes phentylamine, dopamine
  2. Monoamine hypothesis of depression
    • deficit in 5-HT, NE, and DA in depression
    • first gen anti-depressants were MAO inhibitors (too many peripheral adverse events, now only used if resistant to SSRI)
  3. MAO and aggression
    Some individuals with low/no levels of MAO-A are prone to aggression, especially males
  4. Mao-B inhibitors
    • Ex. deprenyl
    • similar to phenthylamine and increases brain DA levels (used in PD treatment adjunct to L-dopa)
  5. Hypertensive crisis
    • caused by MAO inhibitors
    • hyperadrenergic state induced by MAO-I and pressor amines (like tyramine, found in cheese, beer, wine, soy sauce)
  6. How to inhibit ALDH
    disulfiram (antabuse) or cyanide
  7. ALA synthetase induced by:
    heme deficiency due to excess p450 synthesis, erythropoietin, acute intermitten porphyria or ALA dehydratase deficiency
  8. What happens when ALA (aminolevulinic acid) synthesis increases?
    • increased ROS , supraoxide radical, and NH4. 
    • Increased 4,5-dioxocaleric acid (DOVA), which can cause DNA adducts and liver cancer.
  9. How does erythropoietin induce hemoglobin synthesis in bone marrow?
    Erythropoietin in nuclei activates transcription of ALAS2 gene, ALAS-mRNA synthesis, transferrin receptor gene. 

    Iron binds to IRE-BP of ALAS-mRNA, this induces synthesis of ALAS mRNA which is translated to ALAsynthase protein. ALAS involved in heme synthesis in mitochondria, which will bind globin in the cytosol to make hemoglobin.
  10. Step 1 of Heme synthesis
    • Succinyl CoA+ glycine -> Aminolevulinic acid
    • In mitochondrial matrix
  11. Step 2 of heme synthesis
    • ALA -> Coproporphyrinogen III
    • in the cytosol
  12. Step 3 of heme synthesis
    • Coproporphyrinogen III -> HEME
    • mitochondrial matrix
  13. Oxidative degradation of heme to bilirubin
    • takes place in the liver
    • heme toxin oxidized to bilirubin
    • bilirubin further detoxified by glucoronidation or albumin
  14. Biliverdin and Bilirubin. Which one is fat soluble? Which one is excreted by reptiles? Which one is a neurotoxin to babies?
    • Biliverdin is water soluble, bilirubin is fat soluble
    • Biliverdin excreted by reptiles/birds
    • Bilirubin is a neurotoxin to babies
  15. What is ligandin?
    a GSH transferase on hepatocyte surface that traps bilirubin from plasma and helps transport it to the liver where it is glucoronidated . Conjugated bilirubin leaves through the bile.
  16. Gilbert's syndrome
    causes jaundice (buildup of bilirubin)- caused by genetic mutation in activity of glucoronosyl transferase