Eicosanoids And Disease Flashcards
1
Q
Eicosanoids
A
- Term for biologically active lipid compounds based on 20C fatty acids and their metabolites
- Can be obtained from n-6 or n-3 20C fatty acids
- Signalling molecules made by enzymatic and non-enzymatic oxidation of Polyunsaturated Fatty Acids or Arachidonic acid
- Action mediated by cAMP causing them to act in similar mechanisms as hormones
- Act as local mediators (autocrine manner), act where they are produced, however true hormones are secreted into blood and travel to target cell
2
Q
Subfamilies of Eicosanoids
A
- Prostaglandins (produced by most cells)
- Thromboxanes (produced by most cells)
- Leukotrienes (produced by most cells)
- Lipoxenes
- Risolvins
- Reoxins
3
Q
Physiological actions of Eicosanoids initiate of influence
A
- Inflammatory responses in joints in joints, skin and eyes
- Production of pain and fever
- Regulation of blood pressure
- The induction of blood clotting
- The control of reproductive functions including induction of labour
- The regulation of the sleep wake cycle
4
Q
Arachidonic Acid (precursor, storage and availability)
A
- AA is a 5,8,11,14 Eicosatetranoic acid
- Arachidonic acid is the precursor of prostaglandins
- Arachidonic acid is synthesised from linoleic acid (essential aa)
- Can also be derived from DAG
- Stored as part of phospholipid structure
- Availability of Arachidonic acid is controlled by enzymatic release from phospholipids
- Phospholipase A2 hydrolyses acyl groups fatty acid at carbon 2 to release arachidonic acid
- Phospholipase C hydrolyses polar group to release it
5
Q
Corticosteroid function
A
-Used as anti-inflammatory agent, inhibits phospholipase A2. This reduces the amount of arachidonic acid released and therefor lowers the level of eicosanoid
6
Q
General pathways responsible for forming Eicasosanoids
A
-The cyclooxygenase pathway which produces prostanoids
-The lipogenase pathway which produces leukotrienes
Leukotrienes = leukocytes+ + trienes - responsible for potent inflammatory responses
7
Q
Cyclooxygenase pathway (Schematic)
A
- Phospholipids–>Arachidonic Acid–>PGG2–>PGH2–>PGD2 or PGE2–>PGF2a
- Phospholipids–>Arachidonic Acid–>PGG2–>PGH2 –>ThrombonxanA2 (TXA2)
- Phospholipids–>Arachidonic Acid–>PGG2–>PGH2–>Prostacyclin (PGI2)
8
Q
Lipogenase pathway (Schematic)
A
Phospholipids–> Arachidonic acid –>Leukotrienes
9
Q
Cyclooxygenase pathway
A
- PGH2 is the immediate precursor of all series 2 Prostaglandins, prostacyclin and thromboxane
- The outcome for PGH2 is dependant on the activates of the enzymes carrying out the conversions
- Platelets contain thromboxane synthase, so can synthesise thromboxane A2 (TxA2) a strong vasoconstrictor and platelet aggregation promotor
- Vascular endothelial cells contain prostacyclin synthase, so can synthesise Prostacyclin I2 (PGI2) a strong vasodilator and inhibitor of platelet aggregation
10
Q
Opposing effects of TxA2 and PGI2
A
- TxA2 and PGI2 act in opposition o each other and maintain the balance of he cardiovascular system
- The first 2 steps in cyclooxyrgenase pathway are catalysed by enzyme - Prostaglandin endoperoxide synthase - has 2 enzyme activities: cyclooxyrgenase and hydroperoxidase catalysing these first 2 steps
11
Q
Mechanism of Non steroidal anti inflammatory drugs (NSAIDS) such as Aspirin
A
- Inhibit the synthesis of prostaglandins, prostacyclin and thromboxanes by inhibiting the cyclooxyrgenase activity
- Aspirin acetylates cyclooxyrgenase, this is a irreversible inhibition
- Other NSAIDs either compete with Arachidonic acid at the active site of cyclooxyrgenase (COX) or by blocking the reaction by taking up a conformation similar to the proxy radical intermediate
12
Q
Lipoxygenase Pathway
A
- Leukotrienes are synthesised by many cells inc. WBC, Mast cells, spleen and the heart
- Modified leukotrienes are now known to be part of what was formerly called the slow reacting substances of anaphylaxis
- These substances work at very low concentrations and they contract intestinal, vascular and respiratory smooth muscle
- Thought to be agents mediating asthma due to constricting the bronchi in the respiratory system and increase many secretions there
- Leukotriene B4 (LTB4) is a potent chemostatic agent (something that attracts motile cells) that draws in white blood cells to fight infection
13
Q
Eicosanoids and Cytochrome p450
A
- Many eicosanoids including Leukotriene B4 are metabolised by cytP450 (exists in many isoforms, some involved with drug metabolism others have a more physiological role)
- CYP4F family of isoforms are responsible for hydroxylating a wide range of substrates
- Hydroxylation mechanism usually tends to represent deactivation
- Omega oxidation is an LTB4 inactivation pathway
14
Q
Pro-inflammatory pathway effect on prostaglandins and leukotrienes
A
- Phospholipids and DAGs –>AA–>Cyclooxyrgenase–>Prostaglandin INCREASE –>CYP4F metabolises
- Phospholipids and DAGs –>AA–>Lipoxygenase –>Leuktrienes INCREASE –>CYP4F metabolises
15
Q
Anti-inflammatory pathway effect on prostaglandins and leukotrienes
A
- Phospholipids and DAGs –>AA–>Cyclooxyrgenase–>Prostaglandin DECREASE –>CYP4F metabolises
- Phospholipids and DAGs –>AA–>Lipoxygenase –>Leuktrienes DECREASE –>CYP4F metabolises
16
Q
Eicosanoids and cancer
A
- Prostanoids have been shown to alter cancer cell proliferation and dead
- They influence angiogenesis
- They increase cell migration and invasion and maintain a state of chronic inflammation
17
Q
PGE2 (Prostaglandin E2) pro carcinogenic effects
A
- Most abundant PG, produced by fibroblasts, leukocytes and renal cells taking part in renal, cardiovascular and reproductive systems
- Main mediator of inflammation and is involved in pathological conditions such as cancer
- Raised levels of PGE2 are found in the following cancers: colon, lung, breast and neck
- Exact biological role has not been established but show it increases survival and proliferation of cancer cells in culture
- Increase in PGE2 conc. related to altered expression in cyclooxygenases (especially COX2), usually overexposes in cancer cells associated with progressive tumour growth and resistance of cancer cells to conventional chemotherapy and radiotherapy
Procarcinogenic effects of PGE2 metabolism
-PG transport protein required from PGE2 breakdown, and enzyme 15-PGDH needed to oxidise PGE2, both have lower expression in cancers
18
Q
TXA2 (Thromboxane A2) pro carcinogenic effects
A
- Plays a central role in homeostasis and is implicated in cancer
- Increased TXA2 in human carcinomas relative to that in normal breast tissues and was related to increased tumour size and metastatic potential
- The TXA2 receptor plays a role in cancer by promoting tumour growth
- Higher levels of TPmRA transcripts were significantly associated with high grade tumours and shorter disease free survival
19
Q
PGF2A (Prostaglandin F2alpha) pro carcinogenic effects
A
- Another prostanoid PGF2a is related to increased migration and invasion in colorectal carcinoma cells
- In prostate cancer, the over expression of aldo-keto reductase 1C3 (AKR1C3) an enzyme involved in PG metabolism, resulting in higher levels of PGF29, a promoter of prostate cancer and increaser of cell resistance to radiation
20
Q
PGI2 (Prostaglandin I2) pro carcinogenic effects
A
- Some recent research suggests PGI2 may protect against cancer development by inhibiting tumour growth, angiogenesis , invasion and metastasis and thus can be considered a potential chemopreventive agent
- However, in the case of breast cancer, expression of PGI synthase is associated with a reduction of patient survival
- these apparently contradictory actions of PGI2 on cell survival may indicate that its affects are highly dependant on the specific cellular environment
21
Q
PGD2 (Prostaglandin D2) pro carcinogenic effects
A
- PGD2, little research into tumour development
- Some evidence for anti tumour activity, studies shown that PGD2 has anti proliferative activities and can induce cellular apoptosis via activation of caspase - dependant pathways in human leukaemia cells and colon cancer cells
- The generation of 15-deoxydelta- 12 - 14PGJ2, a metabolite of PGD2 seems to be the key factor responsible for the apoptosis observed in A549 cells
22
Q
Leukotrienes and 5-HETE (Hydroxyeicosatetranoid Acid)
A
- Leukotrienes and 5-HETE generated by 5-Lipoxygenase play an important role in the inflammatory process associated with numerous diseases
- These include cancer, allergic asthma, dementia, arthitiris , atherosclerosis, ischaema, and septic shock
- 5-LOX shown to play important role in tumour development
23
Q
12 Lipoxygenase (12-LOX) , 12HpETE and 12-HETE
A
- 12-Lox responsible for the insertion of molecular oxygen and fromation of a hydroxmperoxyl group at carbon 12 of AA chain to form 12-HpETE (no known function)
- 12-HpETE is a precursor of 12 HETE and is strongly correlated with metastasis
- 12 HETE activities are triggered through recognition by specific receptors on plasma membrane
- 12 Lox inhibition reduces angiogenesis and metastatic colonisation of the lungs in an animal model
24
Q
15 Lipoxygenase (15 LOX) isoforms, 13-HODE and cancer
A
- 2 isoforms of 15 - lipoxygenase, 15-LOX1 and 15-LOX2
- In colon cancer cells that induced the expression of 15-LOX1 decreased cell proliferation and increased apoptosis
- A study proposing that 15-LOX-1 had antimutagenic role showed decrease in 13-HODE production
- Other studies show a different role for 15-LOX and 13-HODE in the prostate
- Treatment of the prostate cancer cell line PL-3 with HODE led to enhanced MAP Kinase (MAPK) pathway signalling, resulting in increased proliferation
25
Methods n-3 Polyunsaturated fatty acid supposedly prevent cancer cancer
- Reduce COX2 and PGE2 ( decrease tumour cell growth and invasion)
- Increases tumour suppression proteins BRcA1
- Decrease cachexia
- Decrease in protein kinases (JNK, MAPK, p38, NF-Kb)
- Increases PPARalpha and PPRgamma mediated apoptosis
- Regulate Ca2+ channels to activa eIF2a kinase and decreases oncogenes
26
Metastasis, non- enzymatic lipid peroxidation and triple negative breast cancer
- Metastasis is the movement of a cancerous body, from an initial or primary site to a different site within the body
- increased non enzymatic lipid peroxidation can induce apoptosis in tumour cells
- Triple negative breast cancer occurs when the 3 most common receptors known to support most breast cancer growth are not present in the cancer tumour: oestrogen, proestrogen and HER-2/neu gene
27
Disease interactions between Flavanoids and Eicosanoids
- Flavanoids are naturally occurring substances with variable phobic structures and found in fruit, veg, grain, bark, wine, tea etc
- Epidemiological studies have suggested a protective role of dietary flavonoids against coronary heart disease
- Falvanoids have potential health benefits by acting as antioxdants, they are commonly secondary metabolites from plant foods
- Flavanoid intake was shown to be inversely correlated to mortality due to coronary heart disease
- In vitro experimental systems also showed that flavonoids possess anti-inflammatory, anti- allergic, anti-viral and anti-carcinogenic. These are suggestive of a positive role of eicosanoids
Flavonoids fall into 4 main classes
- Flavones
- Flavanones
- Anthocyanins
- Catechins
28
Prostaglandin series formation from Eicosatetranoic acids
1) 8,11,14 Eicosatrienoic Acid
2) 5,8,11,14 Eicosatetranoic Acid (Arachidonic acid)
3) 5,8,11,14,17 Eicosapentanoic Acid
- 8,11,14 Eicosatrienoic Acids form series 1 Prostaglandins
- 5,8,11,14 Eicosatetranoic Acids (Arachidonic acid) form series 2 Prostaglandins
- 5,8,11,14,17 Eicosapentanoic Acids form series 3 prostaglandins
