Transcript HEME CATABOL SM469.5 KB

HEME CATABOLISM
Prof.Dr.Arzu SEVEN
HEME CATABOLISM
•In one day, 70 kg human turns over ~= 6 gr of Hb
•Hb
heme
globulin
iron_free porphyrin
iron (reuse)
amino acid (reuse)
• 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
MAİNLY İN BRAİN γ TESTES
• HO-3
NOT WELL CHARACTERİZED
• Iron is oxidized to ferric form
HEMIN
• 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+3 is released, CO is
produced, tetrapyrole ring is split to form
biliverdin (green).
• 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.
• İts protective effects are important in the
developing brain of newborn infants
• 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
• 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
• 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.
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
• Bilirubin monoglucuronide is an
intermediate, subsequently converted to
diglucuronide.
• Phenobarbital induces
UDP_glucuronosyl_transferase activity
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
• 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)
• 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
• 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 .