Eikozanoidler ve Diger Otakoidler

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Eikozanoidler ve Diger Otakoidler

• Prof. Dr. Hakan KARADAG

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http//www.genome.jp/kegg/pathway/map/map00590.htm
l
http//www.genome.jp/kegg/docs/updnote.html
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Ders Plani

• Siklooksijenaz Ürünleri
• Prostaglandinler
• Prostasiklin (PG I2)
• Tromboksan A2
• Ilaç Olarak Kullanilan Prostaglandinler
• Dinoproston, Dinoprost, Karboprost, Gemeprost,
  Alprostadil, Mizoprostol, Rioprostil, Enprostil,
  Arboprostil, Latanoprost,Travoprost,
  Bimatoprost, Iloprost
• Lipoksijenaz Ürünleri
• Sitokrom P450 Ürünleri
• Nitrik Oksid
• Trombosit Aktive-Edici Faktör (PAF)

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Tarihçe

• Ilk olarak semenden saflastirilmistir (1935).
  (Ulf von Euler)
• Prostat kaynakli oldugu düsünülerek PROSTAGLANDIN
  adi verilmistir.
• Aspirin-benzeri ilaçlarin sentezlerini inhibe
  ettiginin anlasilmasi ile önemi anlasilmistir
  (1971)
• 1982 Nobel Ödülü Sune K. Bergström, Bengt I
  Samuelsson, John R Vane

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Name EFA Type Series
Gamma-linolenic acid (GLA) via DGLA ?-6 series-1
Arachidonic acid (AA) ?-6 series-2
Eicosapentaenoic acid (EPA) ?-3 series-3
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Nomenclature and terminology
Fatty acids are straight chain hydrocarbons
possessing a carboxyl (COOH) group at one end.
The carbon next to the carboxylate is known as a,
the next carbon ß, and so forth. Since biological
fatty acids can be of different lengths, the last
position is labelled ?, the last letter in the
Greek alphabet. Since the physiological
properties of unsaturated fatty acids largely
depend on the position of the first unsaturation
relative to the end position and not the
carboxylate, the position is signified by (?
minus n). For example, the term ?-3 signifies
that the first double bond exists as the third
carbon-carbon bond from the terminal CH3 end (?)
of the carbon chain. The number of carbons and
the number of double bonds is also listed. ?-3
184 (stearidonic acid) or 184 ?-3 or 184 n-3
indicates an 18-carbon chain with 4 double bonds,
and with the first double bond in the third
position from the CH3 end. Double bonds are cis
and separated by a single methylene (CH2) group
unless otherwise noted. So in free fatty acid
form, the chemical structure of stearidonic acid
is Chemical structure of stearidonic
acid showing physiological (red) and chemical
(blue) numbering conventions.
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• Examples
• For a complete tables of ?-3 and ?-6 essential
  fatty acids, see Polyunsaturated fatty acids.
• The essential fatty acids start with the short
  chain polyunsaturated fatty acids (SC-PUFA)
• a-Linolenic acid (183) - ?-3
• Linoleic acid (182) - ?-6
• These two fatty acids cannot be synthesised by
  humans, as humans lack the desaturase enzymes
  required for their production. They form the
  starting point for the creation of longer and
  more desaturated fatty acids, which are also
  referred to as long-chain polyunsaturated fatty
  acids (LC-PUFA)
• ?-3 fatty acids
• eicosapentaenoic acid or EPA (205)
• docosahexaenoic acid or DHA (226)
• ?-6 fatty acids
• gamma-linolenic acid or GLA (183)
• dihomo-gamma-linolenic acid or DGLA (203)
• arachidonic acid or AA (204)
• ?-9 fatty acids are not essential in humans,
  because humans possess all the enzymes required
  for their synthesis. The public is sometimes
  perceived as ignorant of this, as many supplement
  companies market Omega 3-6-9 blends.

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List of omega-6 fatty acids
Common name Lipid name Chemical name
Linoleic acid 182 (n-6) 9,12-octadecadienoic acid
Gamma-linolenic acid 183 (n-6) 6,9,12-octadecatrienoic acid
Eicosadienoic acid 202 (n-6) 11,14-eicosadienoic acid
Dihomo-gamma-linolenic acid 203 (n-6) 8,11,14-eicosatrienoic acid
Arachidonic acid 204 (n-6) 5,8,11,14-eicosatetraenoic acid
Docosadienoic acid 222 (n-6) 13,16-docosadienoic acid
Adrenic acid 224 (n-6) 7,10,13,16-docosatetraenoic acid
Docosapentaenoic acid 225 (n-6) 4,7,10,13,16-docosapentaenoic acid
Calendic acid 183 (n-6) 8E,10E,12Z-octadecatrienoic acid
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Membran Fosfolipidleri
Fosfolipaz A2
ARASIDONIK ASIT
Siklooksijenaz
Sitokrom P450
5 Lipoksijenaz
Prostaglandinler
Sitokrom P450 Ürünleri
12 Lipoksijenaz
15 Lipoksijenaz
Lökotrienler ve Diger
Lipoksijenaz Ürünleri
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Arasidonik asit
PGG2
PGH2
PGI2
TxA2
PGF2a
PGE2
PGD2
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Prostanoidler

• Prostaglandinler
• Prostasiklinler
• Tromboksanlar

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FOSFOLIPIDLER

Arasidonik Asit
Siklooksijenaz (COX) COX1 COX2
PGG2
Prostasiklin sentaz
Tromboksan sentaz
PGH2
PGI2
TxA2
non enzimatik
non enzimatik
Endoperoksit D izomeraz
Endoperoksit E izomeraz
Endoperoksit redüktaz
6-keto PGF1a
TxB2
9-hidroksiprostaglandin dehidrojenaz
6-keto PGE1
PGD2
PGF2a
PGE2
9 hidroksiprostaglandindehidrojenaz
9 ketoredüktaz
PGE2
PGF2a
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• COX1(Konstitütif Form)
• Damar endoteli
• Mide mukozasi
• Böbrek
• Kalp
• Trombosit

COX2gtCOX1 Nimesulid Etodolak Meloksikam
FOSFOLIPIDLER

Arasidonik Asit
COX2gtgtCOX1 Selekoksib Rofekoksib

• COX2
• (Indüklenebilir Form)
• Makrofajlar
• Diger inflamatuar hücreler

Siklooksijenaz (COX) COX1 COX2
PGG2
Prostasiklin sentaz
Tromboksan sentaz
PGH2
PGI2
TxA2
non enzimatik
non enzimatik
Endoperoksit D izomeraz
Endoperoksit E izomeraz
Endoperoksit redüktaz
6-keto PGF1a
TxB2
9-hidroksiprostaglandin dehidrojenaz
6-keto PGE1
PGD2
PGF2a
PGE2
9 hidroksiprostaglandindehidrojenaz
9 ketoredüktaz
PGE2
PGF2a
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Lipoxin From Wikipedia, the free
encyclopedia  Interested in contributing to Wikip
edia?  Jump to navigation, search Lipoxins are
a series of anti-inflamatory mediators. Lipoxins
are short lived endogenously produced eicosanoids
whose appearance in inflammation signals the
resolution of inflammation. During the acute
inflammatory process, the proinflammatory
cytokines such as IFN-? and IL-1ß can induce the
expression of anti-inflammatory mediators such as
lipoxins (LXs) and IL-4, which promote the
resolution phase of inflammation.1 They are
abbreviated as LX, an acronym for lipoxygenase
(LO) interaction products. Lipoxins are derived
from arachidonic acid, an ?-6 fatty acid An
analogous class, the resolvins, is derived from
EPA and DHA, ?-3 fatty acids.2 At present two
lipoxins have been identified lipoxin A4 (LXA4)
and lipoxin B4 (LXB4). Lipoxins, as well as
certain peptides, are high affinity (sub
nanomolar) ligands for the lipoxin A4 receptor
(ALXR), which was first identified based on
sequence homology as the formyl peptide receptor
like receptor (FPRL1). Lipoxin signaling through
the ALXR inhibits chemotaxis, transmigration,
superoxide generation and NF-kB
activation.3 Conversely, peptide signalling
through the same receptor, in vitro, has been
shown to stimulate chemotaxis of PMN and calcium
mobilization.3 The peptides that have ALXR
affinity tend to be signals for leukocyte
migration and subsequent phagocytosis such as
acute phase proteins, bacterial peptides, HIV
envelope proteins and neurotoxic
peptides. Lipoxins are also high affinity
antagonists to the cystienyl leukotriene receptor
1 (CysLT1) to which several leukotrienes (LTC4,
LTD4 and LTE4) mediate their smooth muscle
contraction and eosinophil chemotactic effects.
The CysLT1 receptor is also the site of action
for the asthma drug, Montelukast(Singulair)4
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Resolvins From Wikipedia, the free
encyclopedia  Learn more about using Wikipedia fo
r research  Jump to navigation,
search Resolvins are compounds that are made by
the human body from the omega-3 fatty acids
eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA). They are produced by the COX-2
pathway especially in the presence of aspirin.
Experimental evidence indicates that resolvins
reduce cellular inflammation by inhibiting the
production and transportation of inflammatory
cells and chemicals to the sites of inflammation.
They are released and used immunologically by the
kidneys as a tool against acute renal failure,
when it occurs. Resolvins are sometimes classed
with the eicosanoids.
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FOSFOLIPIDLER
NSAII
Glukokortikoidler

Arasidonik Asit
Siklooksijenaz (COX) COX1 COX2
PGG2
Prostasiklin sentaz
Tromboksan sentaz
PGH2
PGI2
TxA2
non enzimatik
non enzimatik
Endoperoksit D izomeraz
Endoperoksit E izomeraz
Endoperoksit redüktaz
6-keto PGF1a
TxB2
9-hidroksiprostaglandin dehidrojenaz
6-keto PGE1
PGD2
PGF2a
PGE2
Dazoksiben Dazmegral
9 hidroksiprostaglandindehidrojenaz
9 ketoredüktaz
PGE2
PGF2a
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Saliverilme

• Prostanoidler depolanmazlar.
• Sentezlendikleri yerden saliverilirler.
• Sentezlerinin artirilmasi ya da azaltilmasi,
  saliverilen prostanoid miktarini artirir ya da
  azaltir.

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Metabolizma

• PGE ve PGFler
• Sentezlendikleri dokularda ya da kan dolasimi
  sirasinda akcigerler tarafindan metabolize edilir.

• PGI2
• Akcigerde metabolize edilmez.
• Karaciger ve böbrek tarafindan metabolize edilir.
• Ayrica, plazmada enzimatik olmayan bir yikima da
  ugrar.

• TxA2
• Metabolizmasi karmasiktir.
• Enzimatik olmayan hidrolizle TxB2ye dönüsebilir.

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Prostaglandinlerin Etkileri
TxA2 PGF2a PGI2 PGE2 PGE1 PGD2
Damar düz kasi - - - - - -
Trombosit adezyon-agregasyon - - - - - - - - - -
Uterus
Mide asit salgisi ??? ??? ???
Sitoprotektif etki
Bagirsak tonus ve motilitesi ? ???sulu diyare ? ??? sulu diyare ???sulu diyare
Bronslar konstriksiyon gevseme gevseme
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Prostaglandinlerin Etkileri (devam)
TxA2 PGF2a PGI2 PGE2 PGE1 PGD2
Diger Etkiler göz içi sivisi basincinda azalma böbrek kan akiminda artma hipertermi, hiperaljezi, diürezis, böbrek kan akiminda artma hipertermi
Preparat Dinoprost Epoprostenolsodyum Dinoproston Alprostadil
Analoglari Karboprost Latanoprost Travaprost Bimatoprost Unoproston Iloprost Sikaprost Arboprostil Enprostil Gemeprost Rioprostil Mizoprostol
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Alprostadil (PGE1) Ductus arteriosus açikliginin sürdürülmesinde
Epoprostenol sodyum (PGI2) Ekstrakorporeal dolasim (hemodiyaliz ya da kalp cerrahisi) sirasinda pihti olusmasini ve trombosit kaybini önlemek için
Iloprost Sikaprost Periferik vasküler hastalik
Latanoprost Travaprost Bimatoprost Unoproston Açik açili glokom
Mizoprostol Rioprostil Enprostil Arboprostil Peptik ülserli, NSAII kullananlarda antiülser ajan olarak (H2-antihistaminiklere üstün bulunmamislardir)
Dinoproston (PGE2) Dinoprost (PGF2a) Karboprost Gemeprost Aborsiyon, uterus kasici
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Mizoprostol CYTOTEC 200 mg, 28 tablet 11,11
YTL Yan Etkiler Diyare, karin agrisi, dispepsi,
flatulans, bulanti, kusma, vajinal kanama
Latanoprost XALACOM 50 mg latanoprost5 mg
timolol, 2,5 ml göz damlasi 36,64 YTL XALATAN
0,005lik 2,5 ml göz damlasi 28,77 YTL
Travoprost TRAVATAN 40 mg, 2,5 ml göz
damlasi 25,82 YTL
Bimatoprost LUMIGAN 0,3 mg/mL, göz
damlasi 30,97 YTL
Iloprost ILOMEDIN 0,20 mg/ml, 1 ampul 349,30
YTL
Dinoproston PROPESS 10 mg, 1 ovül 81,57
YTL
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Prostaglandin Reseptörleri
Agonistler Antagonistler
DP PGD2
EP PGE2
EP1 EP2 EP3 EP4
FP PGF2a
IP PGI2
TP TxA2 PGG2 PGH2 Ifetroban Ramatroban Daltroban, Sultroban
Tümü 7 transmembranal segmentli, G proteini ile
kenetli reseptördür.
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Prostaglandin Reseptörleri (IUPHAR Siniflamasi)
Agonistler Antagonistler
DP1 PGD2
DP2 PGD2
EP PGE2
EP1 EP2 EP3 EP4
FP PGF2a
IP1 PGI2
TP TxA2 PGG2 PGH2 Ifetroban Ramatroban Daltroban, Sultroban
Tümü 7 transmembranal segmentli, G proteini ile
kenetli reseptördür.
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Membran Fosfolipidleri
Fosfolipaz A2
ARASIDONIK ASIT
Siklooksijenaz
Sitokrom P450
5 Lipoksijenaz
Prostaglandinler
Sitokrom P450 Ürünleri
12 Lipoksijenaz
15 Lipoksijenaz
Lökotrienler ve Diger
Lipoksijenaz Ürünleri
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FOSFOLIPIDLER

15-lipoksijenaz
12-lipoksijenaz
Arasidonik Asit
12-HPETE
15-HPETE
Zilöton
5-lipoksijenaz
5-HPETE
12-HETE
LTA sentaz
SRS-ALTC4LTD4 LTE4
LTC sentaz
non-enzimatik
LTA4
LTC4
5-HETE
g-glutamil transpeptidaz
LTA hidrolaz
LTB4 Güçlü kemotaktik
LTB4
LTD4
dipeptidaz

• LTC4, LTD4, LTE4
• Bronkokonstriksiyon
• Pulmoner kan basinci artisi
• Vazokonstriksiyon (arteriyel)
• Kapiler permeabilite artisi

LTE4
g-glutamil transpeptidaz
LTF4
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Lipoksijenazlar Lipoksijenazlar Lipoksijenazlar
5 12 15
Lökosit
Trombosit
Mast hücresi
Endotel hücresi
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Lökotrien Reseptörleri
Agonistler Antagonistler
BLT LTB4
CysLT1 LTC4 LTD4 LTE4 Zafirlukast Montelukast Pobilukast Pranlukast Ibudilast
CysLT2 LTC4 LTD4gtgt LTE4
Tümü 7 transmembranal segmentli, G proteini ile
kenetli reseptördür.
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Lökotrien Reseptörleri (IUPHAR Siniflamasi)
Agonistler Antagonistler
BLT1 LTB4
BLT2
CysLT1 LTC4 LTD4 LTE4 Zafirlukast Montelukast Pobilukast Pranlukast Ibudilast
CysLT2 LTC4 LTD4gtgt LTE4
OXE
ALX Lipoksin A4
Tümü 7 transmembranal segmentli, G proteini ile
kenetli reseptördür.
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Montelukast LUXAT 10 mg, 28 tablet 53,46
YTLNOTTA 4 mg, 28 tablet 55,28 YTL 5 mg, 28
tablet 55,28 YTL 10 mg, 28 tablet 53,48
YTLONCEAIR 4 mg, 28 tablet 55,28 YTL 5 mg,
28 tablet 55,28 YTL 10 mg, 28 tablet 53,46
YTLSINGULAIR 4 mg, 28 tablet 66,78 YTL 5 mg,
28 tablet 66,78 YTL 10 mg, 28 tablet 66,78
YTL 4 mg, ped 28 sase 66,78 YTL ZESPIRA 4 mg,
28 tablet 53,59 YTL 5 mg, 28 tablet 53,59
YTL 10 mg, 28 tablet 53,48 YTL Yan
Etkiler Gastrointestinal bozukluklar, agiz
kurulugu, asiri duyarlilik reaksiyonlari, ates,
artralji, bas agrisi, uyku bozukluklari
Zafirlukast ACCOLATE 20 mg, 56
tablet 59,03 YTLCARROX 10 mg, 56 tablet 25,84
YTL 20 mg, 56 tablet 51,41 YTL Yan
Etkiler Gastrointestinal bozukluklar, bas agrisi,
asiri duyarlilik reaksiyonlari, artralji,
karaciger enzimlerinde yükselme, hepatit,
trombositopeni
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Nitrik Oksid (NO, EDRF)
Kesif Furchgott ve Zawadzki 1979
L
-
Arjinin


Nitrik Oksit Sentaz (NOS)


NOS Inhibitörleri


L
-
NAME
(N
-
nitroarjinin
-
L
-
metil ester)
G

L
-
NMMA
(N
-
monometil
-
L
-
arjinin)
Nitrik Oksit (NO)

eNOS (endotel)

Kalsiyum ve kalmoduline bagimli
(NOS-3)



bNOS (beyin)

Inhibitörler

(nNOS), (NOS-1)

Glukokortikoidler

b

TGF
, IL
-
4, IL
-
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iNOS (indüklenebilir)
Kalsiyum ve kalmoduline bagimli degil

(NOS-2)
Indükleyiciler


Makrofaj

Sitokinler

a
b
g)

Hepatosit
(TNF
, IL
-
1
, interferon
-

Endotoksin

(Lipopolisakkarid)

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• Etki Mekanizmasi
• Solubl guanilat siklaz aktivasyonuintraselüler
  sGMP ?

NO Saliveren Maddeler Asetilkolin Histamin Serotonin Vazopresin Bradikinin PG I2 VIP P maddesi CGRP Insulin Klonidin (a2-uyari) Katekolaminler (a2-uyari)

• Etkileri
• Düz kas gevsemesi
• Trombosit adezyonu ve agregasyonunun inhibisyonu
• Antiproliferatif etki

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Trombosit Aktive Edici Faktör (TAF, PAF)

• Membran fosfolipidlerinden üretilir.
• Kimyasal yapi 1-alkil-2-asetilgliseril-3-fosfokol
  in

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• Etkileri
• Güçlü vazodilatör (hipotansif etki)
• Pulmoner damar yataginda vazokonstriksiyon
• Kapiler ve venüllerin permeabilitesinde
  artma(Lewisin üçlü yaniti)
• Trombosit agregasyonuTxA2 üretiminde
  artmaTrombosit yikiminin artmasi sonucu
  trombositopeni
• Düz kas kasici etki gastrointestinal brons uter
  us
• Ülserojen

• Üretim
• Trombositler
• Nötrofil ve eozinofil lökositler
• Monositler
• Damar endotel hücreleri
• Mast hücreleri
• Böbrekte mezangial ve interstisyel hücreler

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Basic Structure of Plasmalogens Plasmalogens are
complex membrane lipids that resemble
phospholipids, principally phosphatidylcholine.
The major difference is that the fatty acid at
C-1 (sn1) of glycerol contains either an O-alkyl
or O-alkenyl ether species. A basic O-alkenyl
ether species is shown in the Figure below. One
of the most potent biological molecules is
platelet activating factor (PAF) which is a
choline plasmalogen in which the C-2 (sn2)
position of glycerol is esterified with an acetyl
group insted of a long chain fatty acid.
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En güçlü En güçlü
Ülserojen PAF
Antiagregan PGI2
Bronkokonstriktör ve kapiler permeabilite artisi yapan LTD4
Kemotaktik LTB4
Proinflamatuar ve hiperaljezik PGE2
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2007 Eylül TUS
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2007 Nisan TUS