![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](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
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heme catabolism.pptx
- 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
- 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.
- 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
- 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
- 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