Billirubin Metabolism

By: Taufiq RN
The Concept of Jaundice
Jaundice

Elevation of billirubin in the plasma

Overproduction of Exretion failure of

Billirubin Billirubin
Hemolytic anemias Hepatitis
pancreas cancer
 Human & Animal Hemoprotein
(protein that contain heme)

Protein Function
Hemoglobin Transport oxygen in blood

Myoglobin Storage oxygen in muscle

Cytochrome C Involvement in electron transport

chain

Cytochrome p450 Hydroxylation of xenobiotics

Catalase Degradation of hydrogen peroxide

Tryptophan pyrolase Oxidation of tryptophan

 Catabolism of Heme Produce Bilirubin
In the human adult 1 2 x 108
erythrocytes are destroyed per
hour
In one day, a 70 kg human turn
over + 6 gr of hemoglobin
When hemoglobin is destroyed,
globin is degraded to its
constituent aminoacids and iron
for reuse
Free iron porphyrin also degrade,
mainly in reticulo endothelial cells
of the liver, spleen, and bone
marrow
The catabolism of heme is carried
out in the microsomal fraction of
cells by a complex enzyme system
called heme oxygenase
 Di manusia dewasa 1 2 x 108
eritrosit yang rusak per jam
dalam satu hari, sekitar 70 kg
manusia menyerahkan + 6 gr dari
hemoglobin ketika hemoglobin
hancur, globin adalah ke
aminoacids penyusunnya dan
besi untuk reuse bebas besi
porfirin juga menurunkan,
terutama di sel endotel reticulo
dari hati, limpa, dan sumsum
tulang yang katabolisme heme
adalah dilakukan di fraksi
microsomal dari sel-sel dengan
sebuah kompleks sistem enzim
disebut heme oxygenase
Its estimated that each 1 gr of
hemoglobin yield 35 mg of bilirubin BLOOD Bilirubin + Albumin
The daily bilirubin formation in human
UPTAKE
adult is + 250 350 mg, deriving from
Hb, in efective erythropoisis, and
cytochrome P450
HEPATOCYTES Bilirubin
Bilirubin formed in peripheral
tissues is transported to the CONJUGATION
UDP GlcUA
liver by plasma albumin and
UDP GlcUA
further metabolized by liver
The Bilirubin metabolism process can
be divided into three step: Bilirubin diglucoronide
1. uptake bilirubin by parenchymal liver
cells
2. Conjugation of bil with glucoronate SECRETION
in the endoplasmic reticulum
3. Secretion of conjugated bil into the Bilirubin diglucoronide
bile HEPATOCYTES
 Dengan perkiraan bahwa setiap 1 gr hemoglobin
menghasilkan 35 mg bilirubin
Pembentukan bilirubin sehari-hari manusia dewasa +
menggunakan 200 mg, hb, berasal dari dalam efective
erythropoisis, dan sitokrom p450
Bilirubin yang terbentuk di jaringan perifer diangkut ke hati
dengan albumin plasma lebih lanjut dan mengalami oleh
hati
Proses metabolisme bilirubin yang dapat dibagi menjadi
tiga langkah yaitu penyerapan parenchymal konjugasi
bilirubin oleh sel hati dari bill dengan glucoronate di
endoplasmic retikulum conjugated bill ke dalam sekresi
empedu
Billirubin Uptaken by Liver
One hight affinity side One low
affinity side
25 mg tightly bound/100ml
Plasma; more loosely bound
Antibiotics and other drugs can
compate with bilirubin for the
high-affinity binding side of
albumin
Bilirubin removed from albumin
mediated by facilitated transport
system
Once bilirubin enter hypatocytes ,
it can bind cytosolic protein
(ligandin; glutathion transferase
family)
Prevent efflux of bilirubin back into
the blood stream
 Satu hight afinitas sisi satu afinitas sisi rendah
25 mg terikat erat / 100ml plasma; lebih longgar
terikat
Antibiotik dan obat lain dapat compate dengan
bilirubin untuk high-affinity mengikat sisi albumin
bilirubin dihapus dari albumin dimediasi oleh
difasilitasi sistem transpor
ekali masuk hypatocytes bilirubin , hal ini bisa
mengikat protein ( cytosolic ligandin; glutathion
transferase keluarga ) mencegah penghabisan
bilirubin kembali ke dalam aliran darah
 Bilirubin conjugation
Hepatocytes convert UDP glucose
dehydrogenase
UDP Glucoronic
UDP aciddehydrogen
bilirubin to polar form glucose ase
Readily excreted in the bile
by adding glucoronic acid 2NAD+ 2NADH + 2H+
(conjugation) bilirubin UDP glucoronosyl
Bil
monoglucoronide UDP transferase
monoglucoronid
bilirubin diglucoronide glucor ac + UDP
(mostly excreted in bile) + bil
UDP glucoronosyl
Enzyme that needed at UDP transferase
Bil diglucoronid
+ UDP
the reaction is glucoronyl glucor ac
transferase (located in ER) + bil monogluc
 Hepatocytes mengkonversi bilirubin untuk
bentuk kutub mudah dikeluarkan dalam
empedu dengan menambahkan asam
glucoronic ( konjugasi ) bilirubin
monoglucoronide bilirubin
diglucoronide ( kebanyakan dikeluarkan dalam
empedu )
Enzim yang dibutuhkan di reaksi adalah
glucoronyl transferase ( yang berlokasi di er `
 Bilirubin is Screted into Bile
By active transport (rate
limiting)
MRP-2 (multidrug-
resistance like protein-2)
= MOAT (multispecific
organ anion transporter)
located in membrane of
bile canalicular a
member ATP binding
cassete family
transporter
 Aktivitas menurut tarif perhubungan ( mrp-2
pembatasan ) dengan ( multidrug-resistance =
protein-2 ) multispecific parit ( transporter
anion alat ) yang terletak di bile membran
yang salah satu di antara canalicular
satu yang mengikat atp di transporter
keluarga yang cassete ~
Conjugated Bilirubin is reduced by
Bacteria in Intestinal
Glucoronide are removed by
Beta glucoronidase (bacterial
enzyme) urobilinogen
(colourless)
Urobilinogen is partly
reabsorbed and reexcreted
through the liver
(enterohepatic urobilinogen
cycle)
Normally urobilinogen are
oxidized to urobilin (colored)
and excreted in faeces
Darkening of faeces upon
standing in air is due to the
oxidation of residual
urobilinogens to urobilins
 Glucoronide dibuang melalui beta
glucoronidase ( bakteri enzim )
urobilinogen ( colourless ) urobilinogen adalah
sebagian reabsorbed dan reexcreted melalui
hati ( enterohepatic urobilinogen siklus )
biasanya urobilinogen yang teroksidasi
urobilin ( berwarna ) dan diekskresikan dalam
faeces penggelapan faeces atas berdiri di
udara itu karena adanya oksidasi dari sisa
urobilinogens untuk urobilins ~
 Jaundice
When bilirubin in blood more than 1 mg/dl (17.1
mol/L) hyperbilirubinemia
When concentration of bilirubin exceeds 2 2.5 mg/dl, can
diffuse into the tissues, which then become yellow
(jaundice)
There are two types of hyperbilirubinemia
Retention hyperbilirubinemia
Unconjugated (hydrophobicity) can cross blood brain barier
encephalopathy
Acholuric jaundice only occur in this type of hyperbilirubinemia
Regurgitation hypergbilirubinemia
Conjugated bilirubin (water solubility), can appear in urine
Choluric jaundice (bile pigment in urine) only occur in this type of
hyperbilirubinemia