Most heme is derived from broken down red blood cells, which are degraded over 120 days by the reticuloendothelial system in the liver and spleen. Heme oxygenase enzymes in the liver break down heme into bilirubin, carbon monoxide, and iron. Bilirubin is carried by albumin to the liver and conjugated with glucuronic acid before being secreted into bile and excreted in feces, providing important antioxidant effects. Abnormalities in this heme catabolism and bilirubin excretion pathway can result in different types of jaundice.
Kodo Millet PPT made by Ghanshyam bairwa college of Agriculture kumher bhara...
heme catabolism.pptx
1.
2. Most heme from RBCs (85%) - rest from turnover
of cytochromes, p450s, immature erythrocytes.
RBCs last 120 days, degraded by
reticuloendothelial (RE) system [liver and
spleen].
Microsomal heme oxygenase hydroxylates
methenyl bridge carbon and oxidizes Fe2+ to Fe3+.
Second reaction open ring and release methenyl
carbon as CO.
CO has a vasodilator effect while bilirubin has
an antioxidant effect
Serum albumin carries bilirubin in circulation,
ligandin in hepatocytes.
Bilirubin & its derivative is collectively known as bile
pigments
3.
4.
5.
6.
7.
8. • In animals biliverdin reductase reduces the
methenly bridge between pyrole III and IV to a
methylene group to produce bilirubin. (yellow
pigment)
• 1 gm Hb 35 mg biliburin
• Daily bilirubin formation in human adults =
250-350mg (from Hb +ineffective
erytropoiesis+cyt P450)
9. • Bilirubin formed in peripheral tissues is transported to liver by
albumin
• IN LIVER:
1)Uptake of bilirubin by liver paranchmal cells
2)conjugation of bilirubin with glucuronate in endoplasmic
reticulum
3)secretion of conjugated bilirubin into bile
10. • Uptake of bilirubin by liver
• Bilirubin is only sparingly soluble in water
• İts solubility in plasma is increased by
noncovalent binding to albumin
• Albumin has one high affinity site and one low
affinity site for bilirubin
• In 100 ml plasma = 25 mg bilirubin can be
tightly bound to albumin at high affinity site
11. • Antibiotics and other drugs compete with bilirubin to
bind to high_affinity site of albumin.
• In liver, bilirubin is removed from albumin and taken
up at the sinusoidal surface of hepatocytes by a
facilated transport system.
• In the hepatocytes bilirubin binds to cytosolic
proteins :
ligandin (a family of glutathione s-transferases) and
protein γ_to be kept solubilized prior to conjugation.
12.
13. Conjugation of bilirubin with glucuronic
acid
• Bilirubin is non_polar.
• Hepatocytes convert bilirubin to a polar form
by adding glucuronic acid to it (conjugation)
• Enzyme: glucuronosyl transferase
• Location:endoplasmic reticulum
• Glucuronosyl donor:UDP_GLUCURONİC ACİD
14.
15. Secretion of conjugated bilirubin into bile
• Active transport mechanism
• Rate-limiting for the entire hepatic bilirubin
metabolism
• MRP_2 (multidrug resistance like protein 2)
=
MOAT(multi specific organic anion
transporter)
Location:plasma membrane of the bile
canalicular membrane
16. • A member of the family of ATP_binding
cassette (ABC) transporters
• Inducible by phenobarbital
• Conjugation γ excretion systems behave as a
coordinated functional unit.
• Conjugated bilirubin reaches the terminal
ileum and large intestine.
• The glucuronides are removed by
β_glucuronidases (specific bacterial enzymes)
17. Major differences between unconjugated and conjugated
bilirubin
FEATURE Unconjugated
bilirubin
CONJUGATED
BILIRUBIN
Normal serum level More Less (less than 0.25mg/dl)
Water solubility Absent Present
Affinity to lipids (alcohol
solubilty)
Present Absent
Serum albumin binding High Low
Van den Bergh reaction Indirect (Total minus
direct)
Direct
Reanal excretion Absent Present
Affinity to brain tissue Present (kernicterus) Absent
18. BLOOD
CELLS
LIVER
Bilirubin diglucuronide
(water-soluble)
2 UDP-glucuronic acid
via bile duct to intestines
Stercobilin
excreted in feces
Urobilinogen
formed by bacteria KIDNEY
Urobilin
excreted in urine
CO
Biliverdin IX
Heme oxygenase
O2
Bilirubin
(water-insoluble)
NADP+
NADPH
Biliverdin
reductase
Heme
Globin
Hemoglobin
reabsorbed
into blood
Bilirubin
(water-insoluble)
via blood
to the liver
INTESTINE
Catabolism of hemoglobin
unconjugated
19.
20.
21.
22.
23.
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25.
26.
27. Sample Indices Normal Obstructive
Jaundice
Hemolytic
Jaundice
Hepatic
Jaundice
Serum Total Bil <1mg/dl >1mg/dl >1mg/dl >1mg/dl
Direct Bil 0~0.8mg/dl ↑↑ ↑
Indirect Bil <1mg/dl ↑↑
Urine Color normal deep deeper deep
Bilirubin — ++ — ++
Urobilinogen a little ↓ ↑ uncertain
Urobilin a little ↓ ↑ uncertain
Stool Color normal Argilous
(complete
obstruction)
deeper lighter or
normal