HEME CATABOLISM Prof.Dr.Arzu SEVEN

HEME CATABOLISMIn one day, 70 kg human turns over = 6 gr of Hb

Hb heme iron_free porphyrin iron (reuse)

globulin amino acid (reuse)

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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).

HO-1 highyl regulated, induced by a wide range of stress conditions (shear stress, angiogenesis, hypoxia, heat shock, UV light, H2O2)HO-2 MANLY N BRAN TESTESHO-3 NOT WELL CHARACTERZEDIron is oxidized to ferric form HEMIN

Hemin is reduced to heme by NADPH.O2 is added to _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

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)

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 .

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

Bilirubin formed in peripheral tissues is transported to liver by albuminIN 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

Uptake of bilirubin by liverBilirubin is only sparingly soluble in waterts solubility in plasma is increased by noncovalent binding to albumin Albumin has one high affinity site and one low affinity site for bilirubinIn 100 ml plasma = 25 mg bilirubin can be tightly bound to albumin at high affinity site

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 _to be kept solubilized prior to conjugation.

Conjugation of bilirubin with glucuronic acidBilirubin is non_polar.Hepatocytes convert bilirubin to a polar form by adding glucuronic acid to it (conjugation)Enzyme: glucuronosyl transferaseLocation:endoplasmic reticulumGlucuronosyl donor:UDP_GLUCURONC ACD

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

Secretion of conjugated bilirubin into bile Active transport mechanismRate-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

A member of the family of ATP_binding cassette (ABC) transporters Inducible by phenobarbitalConjugation excretion systems behave as a coordinated functional unit.Conjugated bilirubin reaches the terminal ileum and large intestine.The glucuronides are removed by _glucuronidases (specific bacterial enzymes)

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: ENTEROHEPATC UROBLNOGEN CYCLE

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 .