Download Metabolism of bilirubin and bile salts synthesis (uronic acid pathway

Metabolism of bilirubin and bile salts
synthesis (uronic acid pathway and role of glucuronides)
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Objectives
At the end of the lecture, the student should be able to:
Name the proteins which contain heme
Explain turnover number of erythrocytes
Describe the site of heme degradation
Describe the fate of globin, Fe and porphyrin ring
Discuss the role of microsomal heme oxygenase system– formation of
bile pigments
Appreciate the changing colour of a bruise
Role of uronic acid cycle as a source of glucuronic acid
Excretion of bile pigments
Heme metabolism
Heme is a constituent of:
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Hemoglobin, myoglobin, cytochromes and other heme containing
proteins
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6 g Hb is metabolised/ day
Producing 350 mg bilirubin
Heme metabolism takes place in reticuloendothelial cells of spleen, liver
and bone marrow
Heme oxygenase system
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Globin part of hemoglobin is hydrolysed to produce amino acids which
enter the body’s amino acid pool
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Fe(ous) is oxidised to Fe(ic) and reutilised
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Iron- free porphyrin ring is first converted to biliverdin (green) and then
reduced to bilirubin (orange-red)
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Microsomal heme oxygenase system
Cleaves the porphyrin ring of heme
Requires NADPH as coenzyme
Cyclic tetrapyrrole structure of heme is converted to linear structure
(removal of 1 C atom as CO)
A green pigment-BILIVERDIN– is formed
Biliverdin is then reduced by biliverdin reductase (NAPDH dependent)to
form red-orange bilirubin
Changing colour of a bruise
Conversion of Heme to Bilirubin
Bilirubin
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belongs among linear tetrapyrrols
is excreted mainly with bile
is insoluble in water but gets solubilised after its conjugation, e.g.
with glucuronic acid
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Transport of bilirubin to liver
Hydrophobic nature of bilirubin
Restricted free movement of bilirubin in plasma
forms Non-covalent complex with albumin
Carried to liver due to polar nature of albumin
Separated from albumin
Enters hepatocytes in free form by active process
Binds to ligandin or Z protein
Uronic acid pathway
Inside the hepatocytes, bilirubin is conjugated with glucuronic acid,
which is provided by uronic acid pathway (UAP)
UAP is a minor pathway of carbohydrate metabolism
Glucuronic acid is an important product required for detoxification of
drugs and for conjugation of steroid hormones and bilirubin before
excretion in urine and bile
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Fate of conjugated bilirubin in intestine
Bacterial enzyme beta glucuronidase removes glucuronides from
conjugated bilirubin (deconjugation)
Subsequent reduction of the pigment produces a colourless compound
called urobilinogen (URO)
Most of URO remains in intestine and is excreted in feces as
stercobilinogen
Nearly 20% URO is absorbed from the intestine into portal circulation
(subsequently excreted via kidneys into urine as urobinlin)
A part of URO returns to liver and reaches gut again
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Plasma bilirubin
Total bilirubin = 0.2- 1 mg/dl
conjugated bilirubin = 0.1-0.4 mg/dl
also called direct bilirubin, being water soluble reacts
immediately with diazo reagent
unconjugated (albumin bound) bilirubin is called
indirect bilirubin. Being water insoluble, it has to be first extracted
with methanol and then treated with diazo reagent
Summary
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Bile acids and bile salts
Bile acids (24 C compounds) are synthesised from cholesterol (27 C)
in hepatocytes and stored in gall bladder
Nearly half of the cholesterol in body is converted to primary bile acids –
cholic acid and chenodeoxycholic acid
Primary bile acids lose OH groups to form secondary bile acids
(deoxycholic acid and lithocholic acid respectively)
Bile acids are formed from cholesterol:
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About 1 gram of cholesterol is eliminated from the body per day.
Approximately half is excreted in the feces after conversion to bile acids.
The remainder is excreted as cholesterol.
The primary bile acids are synthesized in the liver from cholesterol.
These are cholic acid and chenodeoxycholic acid.
In the liver, both primary and secondary bile acids are conjugated with
glycine or taurine to form bile salts: thus
Cholic acid + glycine  glycocholic acid
lithocholic acid + glycine  glycolithocholic acid
Cholesterol  bile acids
A) addition of OH group(s) to the steroid ring
B) removal of 3 C atoms from side chain
C) reduction of ring B
D) oxidation in the side chain to form a –COOH group
Cholic acid = 3,7, 12 cholanic acid
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References
Harper’s Medical Biochemistry, 28th ed
D Puri, Textbook of Medical Biochemistry, 2nd ed