Heme Catabolism Flashcards by Meghan May

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

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Where does this occur:

Heme ring opening, heme –> biliverdin –>bilirubin

Macrophage

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Albumin carries bilirubin from macrophage to liver in the ______

and Bilirubin is conjugated with glucuronic acid, excreted in the _______

blood

liver hepatocytes

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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

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Kidney
Conversion of urobilinogen products to_____, excreted
in urine

urobilin

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Understand basic bilirubin metabolism

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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

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What makes poop brown

bacteria; stercobilin

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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

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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.

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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.

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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)

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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

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Endogenous compounds are toxic in their free form:
Fe2+/ 3+ –>bound by___
CO –> bound by____

ferritin

hemoglobin

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Biliveridin to bilirubin via:

biliverdin reductase, which can
use either NADH or NADPH for activity. Bilirubin is less polar (antioxidant during fetal)

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Transports bilirubin, keeps in solute takes to liver from spleen and Kupfner cells

albumin

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Although tightly bound to albumin, bilirubin is rapidly removed from the circulation by ____ Bilirubin dissociates from albumin before entering the
________

the liver.

hepatocyte

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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

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______is the major conjugating group and the reaction is catalyzed by a specific form of uridine diphosphate glucuronosyltransferase (UGT1A1).

Glucuronic acid

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_____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

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mono- (BMG) or diglucuronide (BDG)
smay also bind to

ligandins

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_____ is essential for bilirubin excretion and this process appears to be energy-dependent and shared with other organic anions, except _____

Conjugation

bile salts.

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Has been identified in canalicular membranes and is involved in bilirubin excretion

An ATP-dependent multiorganic anion
transporter (MOAT)

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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