1. HEME CATABOLISM Prof.Dr.Arzu SEVEN

2. HEME CATABOLISM In one day, 70 kg human turns over = 6 gr of Hb Hb heme iron_free porphyrin iron (reuse) globulin amino acid (reuse) ~

3. Heme is the source of bile pigments. Iron free porphrin of heme is degraded in RES (liver,spleen bone_marrow) by microsomal heme oxygenase system. Humans have at least 3 izoenzyems of heme oxygenase (HO).

4. HO-1 highyl regulated, induced by a wide range of stress conditions (shear stress, angiogenesis, hypoxia, heat shock, UV light, H 2 O 2 ) HO-2 MAİNLY İN BRAİN γ TESTES HO-3 NOT WELL CHARACTERİZED Iron is oxidized to ferric form HEMIN

6. Hemin is reduced to heme by NADPH. O2 is added to α_methenyl bridge between pyroles I and II of the porphyrin. Ferrous iron is again oxidized to ferric form. O2 is added, Fe is released, CO is produced, tetrapyrole ring is split to form biliverdin (green). +3

7. In animals biliverdin reductase reduces the methenly bridge between pyrole III and IV to a methylene group to produce bilirubin. (yellow pigment) 1 gr Hb 35 mg biliburin Daily bilirubin formation in human adults = 250-350mg (from Hb +ineffective erytropoiesis+cyt P450)

8. The CO produced by heme oxygenase is toxic at high concentrations, however at very low concentrations generated during heme degradation, it has regulatory and/or signalling functions, it acts as a vasodilatator, less potent than NO. Low levels of CO have regulatory effects on neurotransmission.

9. Bilirubin is the most abundant antioxidant in mammalian tissues and is responsible for the most of the antioxidant activity in serum. İts protective effects are important in the developing brain of newborn infants

10. 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

12. 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

13. 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.

14. 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. Bilirubin monoglucuronide is an intermediate, subsequently converted to diglucuronide. Phenobarbital induces UDP_glucuronosyl_transferase activity

17. 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

18. 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)

19. The pigment is reduced by intestinal bacteria (fecal flora) to urobilinogen (colorless tetrapyrolic compound) A small portion of urobilinogen is reabsorbed and reexcreted through the liver: ENTEROHEPATİC UROBİLİNOGEN CYCLE

20. Some urobilinogen is reabsorbed into the blood and transported to the kidney, where it is oxidized to urobilin(the compound that gives urine its yellow color). Urobilinogen remaining in the intestine is converted to stercobilin, which gives the red_brown color to feces.