Wk5 Liver Metabolism Flashcards
What is the liver doing with nutrients in the fed state:
excess protein/carbs –> blood proteins, glucose, VLDL
What gets added to xenobiotics/waste metabolites in Phase I detoxification reactions:
-OH
gets hydroxylated
What happens in Phase II of detox reaction:
addition of sulfate, methyl groups, glutathione, or glucuronate to the hydroxyl group to form secondary metabolite suitable for excretion.
Important Phase I metabolizing enzymes:
cyt P450 family
**all use NADPH
**all use O2
Detoxifying molecule that gets used up by EtOH:
Glutathione
Early sx of Acetaminophen toxicity:
N/V shortly after ingestion
Most common cause of acute liver failure:
Acetaminophen toxicity
Sx 24-48 after acetaminophen OD:
Aminotransferase levels increase
Lactate dehydrogenase increases
Prothrombin time increases
Sx 72-96 hours after acetaminophen OD:
Jaundice
Hepatomegaly
Bilirubin increases
Encephalopathy/coma
Hypotension
Hypoglycemia; metabolic acidosis
Death by general organ failure
NAPQI
cytotoxic product of acetaminophen conversion by:
CYP2E1
**EtOH induces expression and increases rate
Tx for acetaminophen toxicity?
cimetidine
**out-competes for CYP2E1 binding
-also an H2 blocker
CYP2E1 role in EtOH metabolism:
MEOS pathway –> acetaldehyde
Mech of EtOH liver damage:
Acetaldehyde –> Kupffer cells –> TGF-B, ROS, NO “respiratory burst” –> Stellate cell stimulation –> fibrosis
Liver and glucose relationship in fed state:
insulin + glucose –> liver –> TG’s, Glycogen, glycolysis
Liver and glucose relationship in fasted state:
Glucagon & Epi –> liver –> glycogen degradation + gluconeogenesis –> glucose
Two important intermediates between glycogen and glucose:
Glycogen –> Glucose 1-phosphate Glucose 6-phosphate –> (Gluc-6-phosphatASE) –> glucose
**gluconeogenesis joins at G6P step as well
Enzyme that interconverts G-1-P and G-6-P:
PGM1 – phosphoglucomutase
Path from dietary carbs and FAs to bile salts:
–> acetyl CoA –> cholesterol –> bile salts
**5% production needed – 95% get recycled
Fate of excess dietary carbs:
FAs –> TGs –> VLDL
Source of two N’s needed for Urea synth:
Aspartate
free ammonia
Form of excess Nitrogen transport in the blood after protein degradation in tissues:
Glutamine
**review slide 30
a-KG + NH4 –> glutamate + NH4 –> glutamine
location of this reaction?
muscle
peripheral tissue
Glutamine - NH4 –> glutamate - NH4 –> a-KG
location of this reaction?
where does the free ammonia go?
Liver
urea cycle –> urine
Path of ketone body synthesis in liver:
FA’s –> Acetyl CoA –> Acetoacetate/B-hydroxybuterate –> ketone bodies (blood) –> muscle (uses acetoacetate for energy in extended fasting/starvation)
