Biochemistry: Heme catabolism and Bile salts Flashcards
What causes jaundice or scleral icterus?
Accumulation of elevated bilirubin in the skin or sclera, imparting a yellow color to the tissues
Inherited disorders of bilirubin metabolism
Hyperbilirubinemia
How much of heme catabolism comes from senescent erythrocytes? How much comes from turnover of RBCs?
80% - senescent erythrocytes
20% immature RBCs
What is the average lifespan of a RBC and what happens when it reaches this?
120 days – it is taken up by macrophages of the reticuloendothelial system of the liver and spleen
Where does heme ring opening occur?
In the macrophage
Which enzyme selectively cleaves the ferroprotoporphyrin IX ring at the alpha-methelene bridges? What is required for this step?
HO-1 (heme oxygenase)
Needs electrons from NADPH cytochrome P450 oxidoreductase
What is the only known reaction in human tissues that produces CO?
The second step of heme catabolism where there is non-enzymatic oxidation by molecular oxygen
What results in the green pigment of biliverdin?
The release of iron after addition of electrons
Fe2+/Fe3+ and CO are toxic in their free form. What do they bind to avoid toxicity?
Fe2+/Fe3+ binds ferritin
CO binds hemoglobin
What is the enzyme that converts biliverdin to bilirubin? Where does this occur?
Biliverdin reductase
Occurs in the macrophage
*Can use either NADH or NADPH for activity
How does bilirubin differ from biliverdin?
Bilirubin is much less polar than biliverdin and it can cross membranes more readily
Why is bilirubin thought to be particularly important during the neonatal period?
It is also an antioxidant and other antioxidants are relatively low during the neonatal period
What protein does bilirubin bind to travel in the circulation?
Albumin – helps transport bilirubin from primary site of production (red pulp macrophages of the spleen and Kupffer cells of the liver) to its site of excretion (liver)
Where does uptake, storage, conjugation and excretion of bilirubin occur?
In the liver
How is bilirubin kept in solution once it is inside the hepatocyte?
Through interactions with ligandins – this prevents bilirubin from leaving the liver and going back into the circulation and it is a form of temporary storage for the hepatocyte.
What is the enzyme that catalyzes the addition of glucoronic acid to bilirubin? Why does this happen?
UGT1A1 = uridine diphosphate glucuronosyltransferase
This happens to make bilirubin more polar so that it can be excreted across the bile canaliculus
Where is UGT1A1 located?
In the ER of the hepatocyte
What ATP-dependent transporter is involved in bilirubin excretion?
MOAT = multiorganic anion transporter (this is an energy dependent process)
What happens when conjugated bilirubin reaches the intestinal tract?
It is NOT substantially reabsorbed – instead it is degraded by intestinal bacteria into urobilinogen products (which are present in the deconjugated state – not sure when deconjugation happens)
Urobilinogen products = stercobilin (feces) and urobilin (urine)
What is the name of the assay that allows for direct quantification of serum bilirubin?
van den Bergh assay
How does the van den Bergh assay categorize bilirubin into direct and indirect reacting species?
Only the water soluble, conjugated bilirubin reacts rapidly in this assay – this will give you a value for direct bilirubin
The unconjugated, water insoluble bilirubin reacts slowly and is not detected in short incubations.
When this assay is conducted in methanol, both forms of bilirubin react rapidly and this will give you a value for total bilirubin. Therefore, indirect bilirubin can be calculated.
Total - Direct (conjugated) = Indirect (unconjugated)
What are three factors that may contribute to neonatal jaundice in the first 5 days of life?
- Low activity of UGT1A1
- Decreased excretory capacity of hepatocytes
- Increased bilirubin production secondary to accelerated destruction of fetal erythrocytes
What is the specific form of brain damage due to hyperbilirubinemia?
Kernicteris – causes athetoid (writhing) cerebral palsy and often hearing loss
What is the therapy for neonatal jaundice?
Phototherapy – bilirubin light in the blue-green spectrum changes the configuration of bilirubin that can be excreted in bile without conjugation
Absent expression of UGT1A1
Crigler-Najjar syndrome type I
Markedly reduced (<20%) expression of UGT1A1
Crigler-Najjar syndrome type II
Reduced (~30%) expression of UGT1A1
Gilbert Syndrome
Defect in the organic ion transport (MOAT defect) – inability of hepatocytes to secrete conjugated bilirubin into the bile canaliculi after it has been formed –> conjugated bilirubin returns to the blood
Autosomal recessive
Dark pigment to the liver
Dubin-Johnson syndrome
What are some other causes of jaundice?
Hemolytic = increased indirect/unconjugated
Obstructive = increased direct/conjugated
Hepatocellular = increased indirect/unconjugated
What is the precursor of bile acids?
Cholesterol –bile acids represent a major mechanism by which cholesterol is excreted
What is the function of bile acids?
They act as emulsifying agents to prepare dietary triglycerides for hydrolysis by pancreatic lipase and they facilitate absorption of fat-soluble vitamins form the intestine
What are the most abundant bile acids?
Derivatives of cholic acid
What are the primary bile acids?
Primary bile acids are synthesized in hepatocytes directly from cholesterol = cholic acid & chenodeoxycholic acid
What are the secondary bile acids?
Made form primary bile acids by bacteria in the gut via dehydroxylation reactions = deoxycholic acid and lithocholic acid
What is conjugation of bile acids?
It forms bile salts by adding a glycine or taurine – this makes them have a lower pKa value and more soluble
Why are bile acids more than 95% efficient?
They are reabsorbed through enterohepatic circulation and returned to the liver for recycling (12-32g per day)
What is familial hypercholesterolemia?
- elevated concentration of LDL in the plasma
- deposition of LDL-derived cholesterol in tendons and skin (xanthomas) and in arteries (atheromas)
- inheritance is autosomal dominant
**Defect in the gene encoding the LDL receptor
How common is FH?
Heterozygotes number 1 in 500 making it among the most common inborn error in metabolism
How does the LDL receptor limit LDL production?
It enhances the removal of the precursor to LDL, IDL, from the circulation
What are some treatments for FH?
- Bile acid binding resins: prevent cholesterol absorption in the ileum and increases fecal excretion of bile acids to increase the conversion of cholesterol to bile acids in the liver –> liver responds by increasing the production of LDL receptors
- HMG-CoA reductase inhibitors (statins)
- Diet low in cholesterol and fats
