Eicosanoid Biochemistry

Question 1

Eicosanoids

Answer 1

. Signaling molecules formed through enzymatic oxygenation and intramolecular cycle action of long-chain polyunsaturated fatty acids released from membrane phospholipids

Question 2

Major classes of eicosanoids

Answer 2

. Prostaglandins (PG)
. Thrombocytes (TX)
. Luekotrienes (LT)

Question 3

1 series eicosanoids

Answer 3

. PGs and TXs

. Derived from dihomo-gamma-linolenic acid (20:3(8,11,14))

Question 4

2 series eicosanoids

Answer 4

. Derived from arachidonic acid (20:4(5,8,11,14))

Question 5

3 series eicosanoids

Answer 5

Derived from eicosapentaenoic acid (20:4(5,8,11,14,17))

Question 6

Most common precursor of eicosanoids

Answer 6

Arachidonic acid

Question 7

Synthesis of eicosanoids

Answer 7

. Release arachidonic acid from phospholipids in membrane to cytosol via phospholipase A2
. Metabolized by 1 of 3 pathways to form PG, TX, to LT
. Pathway depends on cell type and type of stimulus initiating biosynthesis

Question 8

Cycle-oxygenase pathway for PG and TX

Answer 8

. Oxygenation of arachidonic acid at 20:4 to form unstable PGG2 via COX 1 and 2
. Reduction of OOH on C15 to OH forming unstable PGH2 by peroxidase activity of PGH synthase that glutathione dependent
. Conversion to prostacyclin PGI2 via PGI synthase or thromboxane TXA2 via TXA synthase

Question 9

Regulation of PGH synthase

Answer 9

. Pos: COX-1
. Neg: COX-2
. Peroxidase activity GSH-dependent

Question 10

Lipoxygenase pathway

Answer 10

. Incorporating molecule of oxygen to form unstable 5-HPETE, 12-HPETE, or 15-HPETE (tissue specific) via either 5, 12, or 15-lipoxygenase
. HPETEs converted to HETEs, lipoxins, or LT
. For LT synthesis HPETE converts to corresponding epoxied LTA4
. Further metabolism to LTB4 or LTC4/LTE4 is glutathione-dependent

Question 11

Cytochrome P450 epoxygenase pathway

Answer 11

. Cytochrome P450-dependent oxygenation of 20:4
. Needs NADPH and oxygen
. Uses epoxygenases and hydrolases to make EETs, DHETs, and HETES
. DHETs can be seen in cardiovascular disease, DM, and kidney disease

Question 12

Non-enzymatic formation of oxygenation of arachidonic acid

Answer 12

. Makes isoprostanes (prostaglandin-like compounds)
. Formed via non-enzymatic oxidation of membrane-esterified arachidonic acid by ROS
. Phospholipase A2 releases isometric forms of prostaglandins into circulation
. Serve as markers of lipid oxidant damage, some have bioactivity

Question 13

Eicosanoid mechanism of action

Answer 13

. Efflux of eicosanoids via ABC-type transporters
. Bind to prostanoid receptors (G-proteins)
. OR bind to nuclear receptors (PPAR) and affect gene expression
. Short distance signaling molecules via auto rinse and paracrine secretions

Question 14

How is signaling molecule PAF formed?

Answer 14

. Lyso-PC produced during release of 20:4 from phospholipids
. Converted to PAF

Question 15

ABC-type transports

Answer 15

. ATP-binding cell transporter
. Multi drug resistance assoc. proteins
. Example: MDR

Question 16

organs and tissues effected by eicosanoids

Answer 16

. Smooth muscle (GI, vascular, airways)
. Platelets
. Kidney
. Reproduction
. nervous system (fever, sleep, neurotransmission) 
. Inflammation and immunity 
. Bone metabolism 
. Eyes
. Cancer

Question 17

Corticosteroid function

Answer 17

. Dec. inflammation by phospholipase A2 inhibition causes all eicosanoid synthesis

Question 18

When is COX-2 upregulated?

Answer 18

Inflammatory conditions

Question 19

NSAIDS

Answer 19

. Inhibit both COX-1 and 2, causes undesirable long-term effects
. Celebrex is selective COX-2 inhibitor good for patients w/ chronic inflammation
. Vioxx and bextra COX-2 inhibitors but withdrawn from market from adverse side effects

Question 20

Why is dietary consumption of omega-3 fatty acids important?

Answer 20

. Crates altered eicosanoids
. Good for mediating inflammation and disease develope
. Research controversial on whether or not omega-3s prevent cardiovascular disease

Question 21

Prostacyclin

Answer 21

. Produced by vascular endothelial cells
. Inhibits platelet aggregation
. Causes vasodilation

Question 22

Thromboxane

Answer 22

. Produced by platelets
. Stimulate platelet aggregation
. Causes vasoconstriction

Question 23

What organ do LTs have an important role?

Answer 23

Lung function

Question 24

Transporters for PGE2 inside kidney and action caused

Answer 24

. EP1-4 G protein receptors 
. EP1: inc. intracellular Ca
. EP2: 
. EP3: dec. cAMP
. EP2 and 4: inc. cAMP

Question 25

Prostaglandin functions in kidney

Answer 25

. Renal hemodynamics
. Renin release
. Body water balance
. Na balance

Question 26

OGE2 synthetases

Answer 26

. 3 isozymes
. Constitutive: mPGES-2 and cPGES
. Inducible: mPGES-1

Question 27

Induction of renal COX-2 seen in what diseases?

Answer 27

. Obstructive nephropathy
. Acute kidney injury 
. Renal transplant 
. Chronic kidney disease
. Hypertension
. DM
. Lithium nephrotoxicity
. Renal artery stenosis 
. Glomerular diseases 
. Nephrotic disease 
. CHF

Question 28

NSAID side effects

Answer 28

. Gastric bleeding
. Na retention
. Hypertension
. Prolonged bleeding

Question 29

COX-2 inhibitor side effects

Answer 29

. MI

. Stroke

Question 30

Lipoxygenase inhibitors

Answer 30

Zyflo/zileutron

Question 31

Cardiovascular benefits of omega-3 EPA and DHA

Answer 31

. Lower Triglycerides
. Prevent arrhythmia
. Dec. platelet aggregation
. Dec. bp