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Page 1: HEME CATABOLISM

HEME CATABOLISM

Prof.Dr.Arzu SEVEN

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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)

~

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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).

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• HO-1 highyl regulated, induced by a wide range of stress conditions (shear stress, angiogenesis, hypoxia, heat shock, UV light, H2O2)

• HO-2 MAİNLY İN BRAİN γ TESTES• HO-3 NOT WELL CHARACTERİZED• Iron is oxidized to ferric form HEMIN

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• 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

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• 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)

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• 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 .

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• 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

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• 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

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• 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

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• 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.

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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

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• Bilirubin monoglucuronide is an intermediate, subsequently converted to diglucuronide.

• Phenobarbital induces UDP_glucuronosyl_transferase activity

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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

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• 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)

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• 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

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• 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 .


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