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Heme Degradation & HyperbilirubinemiasHeme Degradation & Hyperbilirubinemias
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FATE OF RED BLOOD CELLS
Life span in blood stream is 60-120 days Senescent RBCs are phagocytosed and/or lysedNormally, lysis occurs extravascularly in the reticuloendothelial system subsequent to RBC phagocytosis Lysis can also occur intravascularly (in blood stream)
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Extravascular Pathway for RBC Destruction
(Liver, Bone marrow, & Spleen)
Hemoglobin
Globin
Amino acids
Amino acid pool
Heme Bilirubin
Fe2+
Excreted
Phagocytosis & Lysis
Recycled
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Metabolic pathway of heme degradation to bilirubin and detoxification of bilirubin by glucuronidation.
NADPH O2
NADP+
H2O
NADPH: P450 Reductase
COHemeOxygenase
NADPH NADP+
Fe2+
NADPH
NADP+
NADPHBiliverdinReductase
UDP-glucuronic acidUDP
UDP-glucuronosyl transferase
(M=methyl,V=vinyl and P=propionate represent heme side chains
JAUNDICEAntioxidant, but at high concn. TOXIC TO NEONATALBRAIN MITOCHONDRIA
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Formation of bilirubin• the iron has usually been
oxidized to the ferric form, constituting hemin.
• first step catalyzed by the microsomal heme oxygenase system.
• the hemin is reduced to heme with NADPH,
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2,Cont• with the aid of more NADPH, oxygen is added to the α-methenyl bridge between pyrroles I and II.
• ferrous iron is again oxidized to the ferric form.
• presence of NADPH and O2, the enzyme adds a hydroxyl group to the methenyl bridge between two pyrrole rings, with a concomitant oxidation of ferrous iron to Fe3+.
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3, cont
• A second oxidation by the same enzyme system • results in cleavage of the porphyrin ring. The green
pigment biliverdin is produced as ferric iron and CO are released
• The CO has biologic function, acting as a signaling molecule and vasodilator.]
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4, cont-
• Biliverdin is reduced, forming the red-orange bilirubin. bile pigments.
• 1 g of hb = 35 mg of bilirubin.
• The daily =250–350 mg,
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Degradation of heme STAGE 1Hemoglobin of old erythrocyte trappedin spleen
NH
NH
N NH
CH
CH
CH
OO
NH
NH
NH
NH
CH
CH2
CH
OO
M V M P P M M V
VMMPPMVM
BiliverdinNADPH + H+
NADP+
Biliverdin Reductase
Excreted by Reptilesand birds
HEMEO2 + NADPH
H2O + NADP+
Fe3+
BILIRUBIN(Neurotoxin to babies)
Bone marrow
transferrin
Plasma Serum Albumin Complex LIVER
Modified fromFig. 28-31 Stryer4th Ed.
NEONATAL JAUNDICEBilirubin accumulates in newborns.(destroy with sunlight).
Heme oxygenase (ER)
CO
H2O soluble
exhaled
ANTIOXIDANT
Fat soluble
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uptake, conjugation, and secretion
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Over view of Bilirubin metabolism
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BILIRUBIN TRANSPORT• sparingly soluble in water,
• increased by noncovalent binding to albumin.• . Each molecule of albumin have one high-affinity site and
one low-affinity site for bilirubin. • In 100 mL of plasma, 25 mg at its high affinity• in excess of this quantity ,can be bound only loosely and thus
can easily be detached and diffuse into tissues.
• compete with bilirubin for the high-affinity binding site
antibiotics and other anionic drugs, fatty acids↑, asphaxia, hypoxia and acidosis .
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Liver. metabolism of bilirubin
(1) uptake of bilirubin by liver parenchymal cells,
(2) conjugation of bilirubin with glucuronate in the endoplasmic reticulum,
(3)secretion of conjugated bilirubin into the bile.
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1,uptake of bilirubin by liver parenchymal cells
• In liver, the bilirubin is removed from albumin .• taken up by a carrier-mediated saturable system. • A facilitated transport system• has a very large capacity, does not appear to be
rate-limiting in the metabolism of bilirubin. • the net uptake of bilirubin will be dependent upon
the removal of bilirubin via subsequent metabolic pathways.
• Ligandin (a family of glutathione S-transferases) and protein Y. cytosolic proteins, keep it solubilized prior to conjugation.. prevent efflux of bilirubin back .
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2, Conjugation of Bilirubin.NON- polar ---- polar, bio-medical importance
• adding glucuronic acid•a specific glucuronosyltransferase endoplasmic reticulum.•Through ester linkage, G A to Propionic acid = glucoronoids