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MAO-A vs MAO-B
- A preferentially metabolizes serotonin
- B preferentially metabolizes phentylamine, dopamine
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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)
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MAO and aggression
Some individuals with low/no levels of MAO-A are prone to aggression, especially males
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Mao-B inhibitors
- Ex. deprenyl
- similar to phenthylamine and increases brain DA levels (used in PD treatment adjunct to L-dopa)
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Hypertensive crisis
- caused by MAO inhibitors
- hyperadrenergic state induced by MAO-I and pressor amines (like tyramine, found in cheese, beer, wine, soy sauce)
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How to inhibit ALDH
disulfiram (antabuse) or cyanide
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ALA synthetase induced by:
heme deficiency due to excess p450 synthesis, erythropoietin, acute intermitten porphyria or ALA dehydratase deficiency
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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.
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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.
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Step 1 of Heme synthesis
- Succinyl CoA+ glycine -> Aminolevulinic acid
- In mitochondrial matrix
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Step 2 of heme synthesis
- ALA -> Coproporphyrinogen III
- in the cytosol
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Step 3 of heme synthesis
- Coproporphyrinogen III -> HEME
- mitochondrial matrix
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Oxidative degradation of heme to bilirubin
- takes place in the liver
- heme toxin oxidized to bilirubin
- bilirubin further detoxified by glucoronidation or albumin
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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
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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.
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Gilbert's syndrome
causes jaundice (buildup of bilirubin)- caused by genetic mutation in activity of glucoronosyl transferase
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