Heme Catabolism Flashcards
Approximately 6-7g of hemoglobin are synthesized each day to
replace heme lost through the normal turnover of red blood cells.
In the human body, ____ of the total iron is present as heme iron
in red blood cells.
During heme catabolism, the body has to deal with:
1) handling the_____ products of porphyrin ring cleavage
2) retention, safe mobilization, and re-utilization of____
~70%
hydrophobic
iron
Where does this occur:
Heme ring opening, heme –> biliverdin –>bilirubin
Macrophage
Albumin carries bilirubin from macrophage to liver in the ______
and Bilirubin is conjugated with glucuronic acid, excreted in the _______
blood
liver hepatocytes
Gastrointestinal tract Conjugated bilirubin is converted by bacteria, removal of glucuronic acid (i.e., deconjugated), conversion to\_\_\_\_\_\_
urobilinogen (more water soluble) that goes to kidneys
Kidney
Conversion of urobilinogen products to_____, excreted
in urine
urobilin
Understand basic bilirubin metabolism
Old RBC—> heme–> bilirubin (indirect) goes into plasma and takes a ride with ______ to the hepatocytes
In the liver______ will conjugate teh bilirubin
Bilirubin can go what to _____ or ______
albumin
bilirubine glurornice
to urine (as urobilin)
to bile duct
What makes poop brown
bacteria; stercobilin
Heme is degraded in a series of reactions to produce ______ which is normally
excreted into bile by the liver. Jaundice or icterus results from accumulation of
elevated bilirubin in the skin and sclera, imparting a yellow color to these tissues.
Inherited disorders of bilirubin metabolism lead to_______.
bilirubin
hyperbilirubinemia
Approximately 80% of heme catabolism occurs from _______ and 20% coming from ________ and various cytochromes in nonerythroid tissues. RBCs have an average lifetime of 120 days, after which they are taken up by macrophages of the:
senescent erythrocytes,
turnover of immature red blood cells (RBCs)
liver and spleen.
Bilirubin, an orange pigment derived from the degradation of heme proteins, is a
potentially toxic waste product that is generally harmless because
of binding to serum albumin. However, there are several clinical conditions involving abnormal bilirubin metabolism.
The ferroprotoporphyrin IX ring is selectively cleaved at the - methene bridge. The first step is catalyzed by______ requires electrons from NADPH cytochrome P450 oxidoreductase (CYPOR).
heme oxygenase
(HO-1)
2nd step heme catabolism the: nonenzymatic oxidation by molecular oxygen with the elimination of CO (only known reaction in human tissues and cells that produces(CO) as a by-product of metabolism). The release of___ occurs after addition of electrons and the resulting green pigment
is_____
iron
biliverdin
Endogenous compounds are toxic in their free form:
Fe2+/ 3+ –>bound by___
CO –> bound by____
ferritin
hemoglobin
Biliveridin to bilirubin via:
biliverdin reductase, which can
use either NADH or NADPH for activity. Bilirubin is less polar (antioxidant during fetal)
Transports bilirubin, keeps in solute takes to liver from spleen and Kupfner cells
albumin
Although tightly bound to albumin, bilirubin is rapidly removed from the circulation by ____ Bilirubin dissociates from albumin before entering the
________
the liver.
hepatocyte
Once inside the hepatocyte, bilirubin is kept in solution through interactions with cytosolic proteins, termed______. This inhibits the_____ of bilirubin back
into the circulation and also represents a form of temporary storage within the hepatocyte.
ligandins
efflux
______is the major conjugating group and the reaction is catalyzed by a specific form of uridine diphosphate glucuronosyltransferase (UGT1A1).
Glucuronic acid
_____is specific for bilirubin and is primarily located in the endoplasmic reticulum of the hepatocyte. Either one or two glucuronic acid moieties of UDP-glucuronic acid are transferred onto bilirubin yielding the mono- (BMG) or diglucuronide (BDG) species, respectivel
UGT1A1
mono- (BMG) or diglucuronide (BDG)
smay also bind to
ligandins
_____ is essential for bilirubin excretion and this process appears to be energy-dependent and shared with other organic anions, except _____
Conjugation
bile salts.
Has been identified in canalicular membranes and is involved in bilirubin excretion
An ATP-dependent multiorganic anion
transporter (MOAT)
Bilirubin reaches the intestinal tract mainly conjugated and is not substantially readsorbed. Rather, bilirubin is degraded by intestinal bacteria into a series of______ products.
urobilinogen
Urobilinogens are present in the______ state and it is not known whether this precedes or follows degradation of bilirubin to urobilinogens.
deconjugated
Clinical Lab Test for Serum Bilirubin
Van Den Bergh Assay (allows for direct quantification)
Only the water soluble, conjugated bilirubin reacts
rapidly in this assay,yields a value for_____
bilirubin. Unconjugated, water insoluble bilirubin
reacts slowly, not detected unless you perform the assay in:
direct
Methonal
What type of assay do you conduct to get total bilirubin
in methonal, both conjucated and unconjucated are solbule
How do you calculate Indirect bilirubin?
Total Bili - Direct (conjugated)
Four causes of Unconjucated hyperbilirubenemia
Neonatal jaundice
Crgler-Najjar Type I
Crigler-Najjar Type II
Gilbert Syndrome
Hemolytic
Hepatocellular
What causes direct or conjucated hyperbilirubeninma
Dubin-Johnson
Rotor syndrome
Obstructive issues
Neonatal Jaundice
Serum bilirubin is predominantly unconjugated. If untreated, high bilirubin levels
can damage regions of the brain, such as the
________, involved in controlling muscle movement.
basal ganglia (yellow discoloration)
_______is a specific form of brain damage (“bilirubin encephalopathy”) due to hyperbilirubinemia, causing athetoid (writhing) cerebral palsy and often
hearing loss.
Kernicterus
Tx of neonatal jaundice
phototherapy with light in the blue-green spectrum (430-490 nm; bilirubin can be excreted in bile
without conjugation.
What do teh Hepatic bilirubin UDP glucornosyltransfersase levles look for:
Criger-Najjar I
Crigler-Najjar II
Gilbert
Criger-Najjar I; absent!
Crigler-Najjar II: markedly reduced <20%
Gilbert: reduced ~30%
All three syndromes are related to disorders in UGT1A1 expression, which results in more Unconjugated Bilirubin, and are listed (left to right) in decreasing order of severity.
Crigler-Najjar I (BAD!)
Crigler-Najjar II (not great)
Gilbert; more common
Defects of bilirubin secretion: both syndromes are inherited, but relatively mild.
_____ is thought to be a defect in organic ion transport (MOAT defect).
_____ is rare and not characterized at the molecular level.
Dubin-Johnson
Rotor syndrome
Dublin Johson and Rotor are both _____hyperbilirubeinmia
Whats a way to tell them apart?
Conjucated
Dublin; defect in MOAT and you have grossly BLACK liver
Rotor is rare, no molecular difference
Inability of hepatocytes to secrete conjugated bilirubin into the bile canaliculi after it has been formed. Conjugated bilirubin returns to the blood.
Conjucated hyperbilirubenemia
Excessive erythrocyte destruction results in the formation of bilirubin in amounts exceeding the conjugating ability of the liver and hence its excretion
into the bile. Free bilirubin increases in plasma as a result.
Hemolytic ; causes jaundice; Indrect hyperbilirubenima
Caused by partial or complete blocking of the bile ducts. Conjugated bilirubin is prevented from being excreted into the intestine and consequently appears in increased amounts in the plasma
Obstructive–> Increased DIRECT
Damage to the liver by toxins, poisons, cardiac failure,
or acute or chronic disease impairs the liver’s capacity to conjugate circulating bilirubin and hence excrete it.
Hepatocellular; increased Indirect/unconjucated
Where do we get cholesterol, why is it important?
from diet or made de novo
key for bile acids, steriod hormones, Vit D, lipid bylaters
Bile acids are synthesized from______ in the liver.
Bile acids are secreted into _____, which are specialized channels formed by adjacent hepatocytes.
cholesterol
bile canaliculi
specialized channels formed by adjacent hepatocytes.
bile canaliculi
Bile acids are carried to the GB for storage and then to the small intestine where they are_____.
Bile acids act as_____ agents to prepare dietary
triglycerides for hydrolysis by pancreatic lipase, & they
facilitate absorption of ____
excreted
emulsifying
fat-soluble vitamins
Cholesterol is Excreted Primarily as
Bile Acids
Bile acids are synthesized from _____ in the liver. Most abundant bile acids are derivatives of ______
cholesterol
cholic acid.
Bile acids represent a major mechanism
by which cholesterol is excreted: the carbon skeleton of cholesterol is notdegraded (oxidized to CO2 and H2O) in humans but
is excreted in bile as
free cholesterol and as bile acids
Cholic acid and Chendeoxycholic acid are both:
where are they made?
Primary bile acids
made in hepatocytes from cholesterol
deoxycholic acid & lithocholic acid are:
How are they made?
secondary bile acids
made when primary are converted to secondary by gut bacteria
Primary and secondary bile acids are reabsorbed by the intestine (lower ileum) into portal blood, and taken up by hepatocytes where they are conjugated to
_____ or ______, forming bile salts
glycine or taurine
Why is conjucation of bile acids important?
it converts the bile acids into molecules (i.e., bile salts) with a lower pKa value. The lower
pKa of bile salts = more soluble in the small intestine
Bile acids act as emulsifying agents to prepare dietary
triacylglycerols for hydrolysis by_____They alsoacilitate the absorption of ____ from the intestine.
pancreatic lipase.
fat-soluble vitamins (vitamin D)
Bile acids reabsorbed and returned to liver for
recycling (>95% efficiency)
(12-32g per day)
The capacity of the liver to produce bile acids is insufficient to meet physiological demands,
so the body relies on an efficient _____that carries bile acids from the intestine back to the liver
enterohepatic circulation
Major mechanism of cholesterol excreation
feces: 0.2–0.4 g/day
1) elevated concentration of LDL in the plasma
2) deposition of LDL-derived cholesterol in tendons and skin (xanthomas) and in arteries (atheromas)
3) inheritance as an autosomal dominant trait with a gene dosage effect (homozygotes are more severely affected than heterozygotes)
Familial Hypercholesterolemia (FH)
Defect in FH is a mutation in the gene encoding the
LDL receptor.
Heterozygotes of FH number 1 in 500 persons, placing FH among the most common inborn errors of metabolism. Heterozygotes have ____elevations
in plasma cholesterol from birth.
twofold
1) LDL receptor limits LDL production
by enhancing the removal of the
precursor, _____from the circulation.
2) LDL receptor enhances LDL____ by mediating cellular uptake of LDL (apo B-100).
IDL (B-100, apo E higher affinity for LDL receptor),
degradation
How do you tx FH?
stimulating the single normal LDL receptor
Bile acid binding resins (cholestyramine and colestipol) –bind biles acids in the intestinal lumen, preventing their absorption from the ileum
2) HMG-CoA reductase inhibitors (statins
Diet low in cholesterol and fats
