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Heme Degradation & HyperbilirubinemiasHeme Degradation & Hyperbilirubinemias
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)
Extravascular Pathway for RBC Destruction
(Liver, Bone marrow, & Spleen)
Hemoglobin
Globin
Amino acids
Amino acid pool
Heme Bilirubin
Fe2+
Excreted
Phagocytosis & Lysis
Recycled
5
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
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,
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+.
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.]
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,
10
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
uptake, conjugation, and secretion
Over view of Bilirubin metabolism
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 .
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.
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 .
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
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