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Porphyrins & Bile Pigments

FY WIDODO

University of Wijaya Kusuma Surabaya

Medical Faculty

Department of Biochemistry

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MEMBUAT RANGKUMAN KULIAH

MANFAAT YANG BISA DIAMBIL DARI MATERIKULIAH INI (BERSIFAT KLINIS)

MINIMUM 3 HALAMAN FOLIO, MAKSIMUM 5HALAMAN FOLIO UNTUK 2 MATA KULIAH, PORFIRINDAN PURIN/PIRIMIDIN

TULISAN TANGAN !!!

TULIS NAMA, NPM, MATERI KULIAH, NAMA DOSEN

DISERAHKAN PALING LAMBAT 1 MINGGU SETELAHSELESAI KULIAH PORFIRIN/PURIN / PIRIMIDIN

TUGAS KULIAH

PORFIRIN/PURIN/PIRIMIDIN

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PORFIRIN Cyclic compounds formed by the linkage

of four pyrrole rings through methyne (HC =) bridges

Formation of complexes with metal ions

bound to the nitrogen atom of the pyrrole

rings

Examples of Some Important Human Hemoproteins

Protein Function

Hemoglobin Transport of oxygen in blood

Myoglobin Storage of oxygen in muscle

Cytochrome c Involvement in electron transportchain

Cytochrome P450 Hydroxylation of xenobiotics

Catalase Degradation of hydrogen peroxide

Tryptophan

pyrrolase Oxidation of tryptophan

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A (acetate)P (propionate)

M (methyl)

Addition of iron to protoporphyrin

to form heme. V (vinyl) = CHCH2.

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Formation of Heme

The two starting materials are succinyl-CoA and glycine

Pyridoxal phosphate "activate" glycine Condensation reaction between succinyl-CoA and glycine a-amino-

b-ketoadipic acid d-aminolevulinate (ALA)

Enzyme: ALA synthase

decarboxilation

MITOCHONDRIA

Two molecules of ALA are condensed by the enzymeALA

dehydratase to form two molecules of water and one of

porphobilinogen (PBG)ALA dehydratase is a zinc-containing enzyme and is

sensitive to inhibition by lead, as can occur in lead

poisoning.CYTOSOL

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The formation of a cyclic tetrapyrroleie, a porphyrinoccurs by

condensation of four molecules of PBG

These four molecules condense in a head-to-tail manner to form alinear tetrapyrrole, hydroxymethylbilane (HMB)

Enzyme: uroporphyrinogen I synthase = porphobilinogen(PBG)deaminase = HMB synthase

cyclizes spontaneously uroporphyrinogen I HMB

uroporphyrinogen III synthase uroporphyrinogen III

These compounds are colorless (porphyrinogens) auto-oxidizedporphyrins (colored).

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uroporphyrinogen Iuroporphyrinogen decarboxylase

coproporphyrinogen I

uroporphyrinogen III coproporphyrinogen III

Acetate (A) methyle (M) : decarboxylated by

uroporphyrinogen decarboxylase

coproporphyrinogen III

coproporphyrinogen oxidaseprotoporphyrinogen III

protoporphyrinogen IIIprotoporphyrinogen oxidase

protoporphyrin III

Requires molecular oxygen. Protoporphyrin III + Fe2+Heme

Enzyme: ferrochelatase (heme synthase)

cytosol

mitochondria

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Decarboxylation of uroporphyrinogens to coproporphyrinogens in

cytosol. (A, acetyl; M, methyl; P, propionyl.)

Heme biosynthesis occurs in most mammalian cells with the exception of

mature erythrocytes, which do not contain mitochondria.

However, approximately 85% of heme synthesis occurs in erythroid

precursor cellsin the bone marrow and the majority of the remainder in

hepatocytes.

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Regulation in Biosynthesis of Heme

ALA synthase occurs in both hepatic (ALAS1) and erythroid (ALAS2)

forms The rate-limiting enzyme:ALAS1feedback inhibition

Heme (-) ALAS1 Heme (+)ALAS1

Aporepressor molecule + Heme

negative regulator of the synthesisof ALAS1

Drugs (eg, barbiturates, griseofulvin) increase in ALAS1.

Most of these drugs are metabolized by a system in the liver that

utilizes cytochrome P450

Glucose can prevent derepression of ALAS1 in liver as can the

administration ofhematin (an oxidized form of heme).

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PORPHYRIAS

Disorders due to abnormalities in the pathway of biosynthesis of

heme genetic or acquired

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Enzyme Involved Type, Class, Major Signs and

Symptoms

Results of Laboratory

Tests

ALA synthase (erythroid

form)

X-linked sideroblastic

anemia3 (erythro-poietic)

Anemia Red cell counts and

hemoglobin decreased

ALA dehydratase ALA dehydratase defi-

ciency (hepatic)

Abdominal pain,

neuropsychiatric

symptoms

Urinary ALA and

coproporphyrin III

increased

Uroporphyrinogen I

synthase

Acute intermittent

porphyria (hepatic)

Abdominal pain,

neuropsychiatric

symptoms

Urinary ALA and PBG

increased

Uroporphyrinogen IIIsynthase

Congenital erythropoietic(erythropoietic)

No photosensitivity Urinary, fecal, and red celluroporphyrin I increased

Uroporphyrinogen

decarboxylase

Porphyria cutanea tarda

(hepatic)

Photosensitivity Urinary uroporphyrin I

increased

Coproporphyrinogen

oxidase

Hereditary

coproporphyria (hepatic)

Photosensitivity, abdo-

minal pain, neuropsy-chiatric symptoms

Urinary ALA, PBG, and

coproporphyrin III and fecalcoproporphyrin III increase

Protoporphyrinogen

oxidase

Variegate porphyria

(hepatic)

Photosensitivity, abdo-

minal pain, neuropsy-

chiatric symptoms

Urinary ALA, PBG, and

coproporphyrin III and fecal

protoporphyrin IX increased

Protoporphyrinogen

oxidase

Variegate porphyria

(hepatic) (MIM 176200)

Photosensitivity, abdo-

minal pain, neuropsy-chiatric symptoms

Urinary ALA, PBG, and

coproporphyrin III and fecalprotoporphyrin IX increased

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In general, the porphyrias described are inherited in an autosomal

dominant manner, with the exception of congenital erythropoietic

porphyria, which is inherited in a recessive mode

The signs and symptoms of porphyria result from either a deficiency of

metabolic products beyond the enzymatic block or from an

accumulation of metabolites behind the block.

If the enzyme lesion occurs early in the pathway, clinically, patients

complain ofabdominal pain and neuropsychiatric symptoms relate

to elevated levels of ALA or PBG or to a deficiency of heme

If the enzyme blocks laterin the pathway result in the accumulation of

the porphyrinogens, their oxidation products, the corresponding

porphyrin derivatives, cause photosensitivity, a reaction to visible light

of about 400 nm The porphyrins, when exposed to light of this

wavelength, are thought to become "excited" and then react with

molecular oxygen to form oxygen radicalsinjure lysosomes and

other organelles release their degradative enzymesskin

damage, including scarring.

The porphyrias can be classified on the basis of the organs or cells

that are most affected: erythropoietic, hepatic & erythrohepatic

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Barbiturates, griseofulvin cytochrome P450 heme ALAS1

porphyria

Diagnosis: clinical and family history, the physical examination, and

appropriate laboratory tests

Treatment: - symptomatic

- to avoid drugs that cause induction of cytochrome P450.

- glucose,hematin may repress ALAS1

- photosensitivity : b-carotene free radicals

Sunscreens

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Katabolisme Heme 12 x 108 erythrocytes are destroyed per hour in 1 day turns over

approximately 6 g of hemoglobin

globin amino acids reused; ironpool Enzyme: complex enzyme system called heme oxygenase

METABOLISME BILIRUBINPENGAMBILAN BILIRUBIN OLEH HATI

Bilirubin hanya sedikit larut dalam plasma & terikat dengan albumin

Obat / antibiotika kompetisi untuk berikatan dg albumin

LIVER: Bilirubin dilepas dari albumin diambil pada permukaansinusoid hapatositSistem Transport Berfasilitas (facilitated transport

system = carrier-mediated saturable system) masuk ke sel hati

berikatan dengan cytosolic protein (ligandin, protein Y). Ikatan ini juga

menjaga agar bilirubin tidak kembali ke aliran darah lagi.

Aktivitas sistem ini menurun pada keadaan patologis

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hijau

kuning

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KONJUGASI BILIRUBIN

LIVER: Bilirubin yang non-polar polar

Konjugasi dengan GLUKORONATBilirubin diglukoronida(conjugated, "direct-reacting" bilirubin) polar

Enzyme: glucuronosyltransferase(dlm retikulum endoplasma) Donor glukuronosil: UDP-glucuronic acid

Enzim dapat diinduksi oleh Phenobarbital Bilirubin diglukoronida diekskresi melalui faeces

when exist abnormally in human plasma (eg, in obstructive jaundice),

they are predominantly monoglucuronides

Obstructive jaundice bilirubin conjugates (predominan

monoglukuronida)

Bilirubin diglukoronida

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METABOLISME BILIRUBIN DALAM USUSDiglukoronida

Bilirubindiglukoronida Bilirubin

Bilirubin direduksi oleh flora ususUROBILINOGEN (tak berwarna)

Sebagian kecil urobilinogen diabsorbsi & diresekresi melalui liver (SIKLUS

ENTEROHEPATIK)

Sebagian besar urobilinogen oksidasiUROBILIN (kuning) faeces

Urobilinogen dlm urine

abnormal

b-glukoronidase Bakteri usus

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Diagrammatic representation of the threemajor processes (uptake, conjugation,

and secretion) involved in the transfer of

bilirubin from blood to bile. Certain proteins

of hepatocytes, such as ligandin (a member

of the glutathione S-transferase family of

enzymes) and Y protein, bind intracellular

bilirubin and may prevent its efflux into the

blood stream. The process affected in a

number of conditions causing jaundice

is also shown.

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HIPERBILIRUBINEMIA

Bilirubin dlm darah >1 mg/dl.

Penyebab: - produksi bilirubin h tidak sebanding dg ekskresi hati- kegagalan ekskresi hati karena:

- kerusakan hati

- obstruksi saluran ekskresi

Bilirubin masuk ke jaringan

Ehrlichs test dari van den Bergh:

- reagen diazo + Bilirubin + etanol senyawa Azo (ungu-merah)

INDIRECT REACTION BILI UNCONJUGATED (FREE)- reagen diazo + Bilirubin (tanpa etanol) senyawa Azo

DIRECT REACTION BILI CONJUGATED Retention hyperbilirubinemia: unconjugated hh

Regurgitation hyperbilirubinemia : conjugated hh

Bili unconjugated dpt menembus blood-brain barrier encephalopathy

Kern icterus

KUNING / ICTERUS / JAUNDICE

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Jaundice

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UNCONJUGATED HYPERBILIRUBINEMIA

A. Hemolytic Anemias

Biasanya ringan (< 4 mg/dL; < 68.4 mmol/L) kapasitas hati besar

utk mengelola bilirubin (uptake, konjugasi, ekskresi)

B. Neonatal Physiologic Jaundice

- Hemolisis > metabolisme bilirubin dlm hati- aktivitas / sintesis UDP-glukoronosil transferase K

- Dpt menyebabkan Kern icterus

- Tx: Phenobarbital +

http://upload.wikimedia.org/wikipedia/en/d/d9/Jaundice_phototherapy.jpg

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C.Crigler-Najjar Syndrome, Type I

- = Congenital nonhemolytic jaundice

- Autosomal resesif; mutasi pada gen pengkode enzim Bilirubin-

UGT UDP-glukoronosil transferase K- Bilirubin bisa sd > 20 mg/dL bilirubin tdk bisa dikonjugasikan

- Klinis: ikterus kongenital berat fatal dalam 15 bulan

- Tx: , liver transplant. Phenobarbital tdk menolong.

D. Crigler-Najjar Syndrome, Type II- Mutasi pada gen pengkode enzim Bilirubin-UGT, tdk seberat

tipe I, bilirubin serum tdk sampai 20 mg/dL

- Dapat di Tx dg Phenobarbital dosisi tinggi

E. Gilbert Syndrome

- Mutasi pada gen pengkode enzim Bilirubin-UGT, sering pada pria

- Klinis tdk berat, aktivitas enzim masih ada sekitar 30 %

F. Toxic Hyperbilirubinemia

- chloroform, arsphenamine, CCl4, acetaminophen, virus hepatitis,

chirrhosis, jamur beracun kerusakan parenkim hati

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CONJUGATED HYPERBILIRUBINEMIA

A. OBSTRUKSI SALURAN EMPEDU

- Penyebab: baru empedu, ca. caput pankreas.- Bilirubin diglukoronida tidak bisa diekskresi regurgitasi ke vena-

vena di liver dan saluran limfe bilirubin masuk ke aliran darah dan

urine (choluric jaundice)

- Cholestatic Jaundice: extrhepatic obstructive jaundice

B. DUBIN-JOHNSON SYNDROME

- Autosomal resesif, mutasi gen MRP-2

- Hepatosit pada area centrilobular mengandung pigmen hitam yang

abnormal yang merupakan derivat epinephrine.

C. ROTOR SYNDROME

- Hiperbilirubinemia terkonjugasi yang kronis, histopatologi hepar tetap

normal

- Etiologi: tdk tahu

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Diagrammatic representation of some major causes of jaundice

Prehepatic indicates events in

the blood stream, the majorcause would be various forms

of hemolytic anemia

Hepatic signifies events in the

liver, such as the various types

of hepatitis or other forms ofliver disease (eg. cancer)

Posthepatic refers to evens in

the billiary tree, the major

causes of posthepatic jaundice

are obstruction of the commonbile duct by a gallstone (billiary

calculus) or bya cancer of the

head of pancreas

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Condition Serum Bilirubin Urine

Urobilinogen

Urine

Bilirubin

Fecal

Urobilinogen

Normal Direct: 0.10.4

mg/dL

Indirect: 0.20.7mg/dL

04 mg/24 h Absent 40280 mg/24 h

Hemolytic

anemia

Indirect h Increased Absent Increased

Hepatitis Direct and

indirect h

Decreased if

micro-obstruction is

present

Present if

micro-obstruction

occurs

Decreased

Obstructive

jaundice

Direct h Absent Present Trace to absent

Laboratory Results in Normal Patients and Patients with Three

Different Causes of Jaundice

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