Liver Detoxification of NH3 and Alcohol (Week 2--Howard) Flashcards
What is ammonia and where does it come from?
NH3 comes from catabolism of AAs released by breakdown of protein in tissues or food
Present in body as ammonium ions (NH4+)
Highly toxic to brain
How are AAs converted to NH3?
50% of AAs in blood are glutamine!
Amine group of AA transfered to alpha-ketoglutarate –> glutamate –> glutamate oxidized to form ammonium and regenerate alpha-ketoglutarate
This happens in liver and kidney
How else can ammonia be produced?
1) Other amino acid oxidases that act on other AAs (other than glutamine) to produce ammonia
2) Bacteria metabolize food in GI tract and produce ammonia
3) Catabolism of catecholamines and nucleotides produces ammonia
4) Glutaminase activity in the kidney produces ammonia to be excreted in urine
Urea Cycle
Main means of disposing of ammonia: convert to urea and excrete by kidney (75%) and intestine (25%)
Urea cycle occurs in liver
HCO3- + NH4+ –> carbamoyl phosphate –> combines with ornithine –> citrulline –> combines with aspartate –> argininosuccinate –> cleaved to fumarate and arginine –> arginine cleaved –> ornithine + urea (excreted) –> ornithine regenerated and starts another round of cycle
“Ordinarily, Careless Crappers Are Also Frivolous About Urination”
Hereditary hyperammonemia
Defect in any of the 5 enzymes in urea cycle
Newborns exhibit psychomotor retardation, stupor, coma
Causes hyperammonemia because ornithine cannot be regenerated!
Treatment of hereditary hyperammonemia
1) Low protein diet
2) Give arginine and other compounds to increase ammonium excretion
3) High calorie diet (prevent breakdown of tissues which creates ammonia)
4) Liver transplant
Compounds that increase nitrogen excretion (for people with hereditary hyperammonemia)
1) Arginine (allows regeneration of ornithine and arginosuccinic acid can be excreted by kidney)
2) Sodium benzoate (conjugates glycine to form hipurric acid which is excreted by kidney)
3) Sodium phenylacetate (conjugates glutamine to form phenylacetylglutamine which is excreted by kidney)
Acquired hyperammonemia
Caused by liver disease (cirrhosis, hepatitis, biliary obstruction)
More common than hereditary hyperammonemia
With severe liver disease:
1) Damaged hepatocytes can’t do urea cycle to produce urea well
2) Portal hypertension causes shunt that bypasses liver, and ammonium absorbed from gut bypasses liver and goes to systemic circulation (toxic to brain)
Possible mechanisms of ammonia toxicity
1) Direct toxic effect of ammonia on ion channels and pumps
2) Increased synthesis of glutamate causes depletion of alpha-ketoglutarate (vital intermediate of citric acid cycle, so now can’t do TCA cycle!) and thus ATP deficiency
Hepatic encephalopathy
Variable clinical features: hypersomnia, coma, slow speech, loss of recent memory, confabulation, personality changes
Mechanism unclear, but could be:
1) Poor hepatic detox of NH3 and mercaptans produced in GI tract
2) Psychoactive compounds produced in brain by acetaldehyde
3) Toxins affect ion pumps and gradients
4) Myelin damage
5) “False” NTs (GABA, tyramine) act as agonists
What causes liver degeneration in an alcoholic?
Metabolism of alcohol adversely affects metabolism of other carbohydrates and induces inflammatory and oxidative stress processes
(Malnutrition is a minor factor even though alcoholics have poor nutrition)
Why are females more susceptible to alcohol-induced cirrhosis?
Females have lower level of alcohol dehydrogenase in stomach, so more alcohol gets to the liver (to damage it)!
Three pathways of alcohol metabolism
1) Alcohol dehydrogenase reaction
2) Microsomal alcohol oxidizing system (MAOS or MEOS)
3) Catalase reaction
How much of alcohol metabolized by liver?
70 - 90%
Alcohol dehydrogenase reaction
Alcohol + NAD+ –> Acetaldehyde + NADH + H+ (via alcohol dehydrogenase)
Acetaldehyde + NAD+ + H2O –> AlcCOOH + NADH + H+ (via acetaldehyde dehydrogenase)
NAD+ is consumed and NADH produced
What is the NAD+/NADH ratio in an alcoholic?
NAD+/NADH ratio in an alcoholic is very low
NAD+ needed for glycolysis (is a cofactor), so alcoholics can’t do glycolysis well
Microsomal alcohol oxidizing system (MAOS)
Uses cytochrome P450 in smooth ER
CYP450 is induced by alcohol
CYP450 inactivates other compounds (drugs)
Consuming alcohol results in induction of CYP450 to metabolize alcohol and other drugs
Drugs whose activity level is affected by alcohol ingestion
Isoniazid (to treat TB)
Halothane (anesthetic)
Acetaminophen (Tylenol–remember, compound NAPQI produced is toxic to liver)
Why do alcoholics have higher incidence of certain cancers?
CYP450 enzyme induced by alcohol converts pre-carcinogens into active carcinogens
Do you always use MAOS (CYP450 enzyme) to metabolize alcohol?
NO!
Only use CYP450 if you drink too much
If just drink a little, only use alcohol dehydrogenase
If you’e an alcoholic (long-term alcohol consumption), what happens to CYP450?
CYP450 is very active no matter what
Catalase reaction
Alcohol + H2O2 –> acetaldehyde + 2H2O (via catalase)
Unimportant (doesn’t happen much) because very low levels of H2O2 in liver
What does alcohol consumption do to CYP450 right away?
It DECREASES the availability of CYP450 to metabolize other drugs (CYP450 can’t work as well bc tied up metabolizing alcohol)
So if you drink alcohol at same time as take Tylenol, CYP450 will NOT metabolize Tylenol (or other drugs) as much
But when you stop drinking alcohol you’re screwed because now CYP450 will metabolize Tylenol like crazy so you’ll get buildup of toxic metabolites
