Eicosanoids and Their Functions

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Questions and Answers

What are eicosanoids primarily derived from?

Dietary carbohydrates

Membrane phospholipids (correct)

Nucleic acids

Amino acids

Which of the following is a precursor for arachidonic acid?

Palmitic acid

Alpha-linolenic acid

Linoleic acid (correct)

Stearic acid

What role do eicosanoids primarily serve in the body?

Store energy

Serve as structural components

Act as local hormones (correct)

Act as neurotransmitters

What is the effect of hormones on the biosynthesis of eicosanoids?

They augment the biosynthesis of eicosanoids. Signup and view all the answers

What is the primary method of activating phospholipases during eicosanoid biosynthesis?

Increased cytolic calcium levels Signup and view all the answers

Which enzyme pathway is responsible for yielding Prostaglandins and Thromboxanes from arachidonic acid?

Cyclooxygenase (COX) pathway Signup and view all the answers

What is the biological impact of eicosanoids on the human body?

They have effects on various systems including cardiovascular and reproductive. Signup and view all the answers

What type of compounds are eicosanoids categorized as?

Small lipid mediators Signup and view all the answers

Which prostaglandin is primarily responsible for strong contraction of uterine smooth muscle?

PGF2α Signup and view all the answers

What is the role of PGF2α during parturition?

Stimulates uterine contraction Signup and view all the answers

Which of the following accurately describes the effects of PGE2 during menses?

It contributes to dysmenorrhea through increased contraction of the uterus. Signup and view all the answers

How does PGE2 influence labor compared to PGF2α?

PGE2 is five times more potent than PGF2α for labor induction. Signup and view all the answers

Which statement describes the effect of PGE2, PGF2α, and their analogs during abortion?

They promote cervical ripening before abortion. Signup and view all the answers

What is a significant consequence of administering synthetic analogs of PGE2?

They can cause cardiovascular collapse. Signup and view all the answers

What is the proposed initiating factor for parturition?

Release of prostaglandins from the placenta Signup and view all the answers

Which of the following prostaglandins acts through Gq proteins and is involved in labor induction?

PGF2α Signup and view all the answers

What is the primary role of phospholipase A2 in the synthesis of eicosanoids?

It releases arachidonic acid from membrane phospholipids. Signup and view all the answers

Which of the following indicates the structural features of prostaglandins?

The letter after PG specifies the side groups on the cyclopentane ring. Signup and view all the answers

What therapeutic action do non-steroidal anti-inflammatory drugs (NSAIDs) primarily exert?

Inhibition of the cyclooxygenase enzymes. Signup and view all the answers

What characterizes the action of glucocorticoids on phospholipase A2?

They induce the synthesis of lipocortin, which inhibits phospholipase A2. Signup and view all the answers

What distinguishes COX-2 from COX-1 in terms of expression?

COX-2 is inducible and expression varies with stimuli. Signup and view all the answers

What are isoprostanes primarily derived from?

Lipid peroxidation of arachidonic acid. Signup and view all the answers

How do cellular proteins such as calpactins influence phospholipases?

They may regulate the activity of phospholipases. Signup and view all the answers

What is the main biological activity of eicosanoids?

They act through specific receptors and enzyme inhibitors. Signup and view all the answers

What conversions occur in the pathway from PGH2 to other prostaglandins?

PGH2 can be transformed enzymatically to TXA, PGI2, PGEs, PGF, and PGD. Signup and view all the answers

What is the primary purpose of using synthetic stable analogs of eicosanoids in clinical settings?

To extend their half-life for effective use. Signup and view all the answers

What is the significance of the symbols following PG in their nomenclature?

They represent various substituents on the cyclopentane ring. Signup and view all the answers

What distinguishes thromboxanes from prostaglandins?

Thromboxanes contain a 6-membered oxane ring. Signup and view all the answers

What is the role of calcium ions in regulating phospholipase A2?

Calcium directly activates phospholipase A2. Signup and view all the answers

Which prostaglandin is known for its role in gastric cytoprotection?

PGE2 Signup and view all the answers

Study Notes

Eicosanoids

Eicosanoids are a family of lipid compounds derived from arachidonic acid
They are extremely prevalent in tissues and fluids throughout the body
Their function is as local hormones
They are synthesized and exert their effects in the same tissue
Also found in plants, possessing potent biological activity

Eicosanoid Types

Prostaglandins
Thromboxanes
Leukotrienes
Related compounds (e.g., platelet-activating factor (PAF))

Eicosanoid Biosynthesis

Derived from membrane phospholipids
Formed from 20-carbon essential fatty acids with 3, 4, or 5 double bonds
Key fatty acids include
- 8, 11, 14-eicosatrienoic acid (dihomo-γ-linolenic acid)
- 5, 8, 11, 14-eicosatetraenoic acid (arachidonic acid)
- 5, 8, 11, 14, 17-eicosapentaneoic acid

Eicosanoid Action

Bind to receptors on target cell plasma membranes in various tissues
Stimulate or inhibit the synthesis of other messengers (e.g., cAMP)
Affect the cardiovascular, pulmonary, reproductive, and digestive systems

Arachidonate

Most abundant precursor
Derived from dietary linoleic acid or ingested as a dietary constituent
Esterified to phospholipids of cell membranes or other complex lipids
Low concentration, so eicosanoid biosynthesis is primarily from cellular stores of lipids via acyl hydroxylases

Eicosanoid Biosynthesis Regulation

Closely regulated and occurs in response to diverse physical, chemical, and hormonal stimuli
Hormones, autacoids, and other substances augment biosynthesis by interfering with plasma membrane-bound receptors coupled to G proteins (Guanine Nucleotide-binding Regulatory Proteins)
This leads to either direct activation of phospholipases (C and/or A₂) or elevated cytosolic [Ca²⁺], activating phospholipases
Physical stimuli can cause Ca²+ influx, activating phospholipase A2

Arachidonic Acid Pathways

Rapidly oxygenated by four distinct enzyme systems
Cyclooxygenase (COX) pathway yields prostaglandins and thromboxanes
Lipoxygenase pathway yields hydroxy/peroxy eicosatetraenoic acid (HETEs), leukotrienes, and lipoxins
Cytochrome P450 pathway yields epoxides
Isoprostane pathway yields isoprostanes

Eicosanoid Inhibitors

Inhibition of Phospholipase A2 decreases the release of precursor fatty acids, reducing metabolite synthesis
Phospholipase A2 is activated by Ca²+ and calmodulin, and inhibited by drugs that reduce Ca²+ availability
Glucocorticoids indirectly inhibit Phospholipase A2 by inducing lipocortin, inhibiting the enzyme
Other cellular proteins, like calpactins, also regulate phospholipases
ASA and related anti-inflammatory drugs inhibit COX

Prostaglandins

Phospholipase A2 hydrolyzes the ester bond to mobilize arachidonic acid from membrane phospholipids
Arachidonic acid is oxygenated and cyclized by prostaglandin endoperoxide synthetases (COX) to form the cyclic endoperoxide PGG₂
PGG₂ converts to PGH₂
PGH₂ is enzymatically transformed by synthases to TXA₂, PGI₂, PGEs, PGF₂, and PGD₂
Interconversion of PGE₂ and PGF₂α is catalyzed by a 9-keto reductase in some tissues

Structural Features of PGs

Letter after PG (e.g., A, B, G, H, F) indicates substituents on the cyclopentane ring
Common conformations are E and F
Subscript indicates the number of double bonds in the side chain

PG Structure

PGE and D series are hydroxy ketones
F series are 1,3-diols
PGA, B, and C series are unsaturated ketones

PG Analogs and Structures

PGs are analogs of prostanoic acid, unsaturated fatty acid derivatives with 20 carbons and a cyclic ring
Prostacyclin (PGI₂) has a double ring structure with a cyclopropane and an oxygen bridge between C6 and C9
Thromboxanes (TX) contain a 6-membered oxane ring rather than a cyclopentane ring

Cyclooxygenases (COX)

Two isozymes (COX-1 and COX-2)
COX-1 is widely distributed and involved in gastric cytoprotection
COX-2 is inducible and its expression varies significantly based on the stimulus, and is involved in immediate early response genes, inflammation, and immune cell function, as well as renal development, and prostacyclin production
NSAIDs exert their therapeutic effect by inhibiting COX activity

PG Receptors

Characteristics of Prostaglandin (PG) receptors. Data presented in table format.

Roles of PGs in Reproductive Processes

PGF₂α strongly contracts uterine smooth muscle
PGE effects vary depending on species and hormonal state

PGs in Parturition and Menstruation

The initiating factor in parturition is likely uterine PGE release from the fetal and maternal placenta.
Dysmenorrhea can be caused by increased endometrial PGE₂ and PGF₂α synthesis during menstruation leading to uterine contraction, causing ischemic pain

PGs in Abortion

PGE₂, PGF₂α, and their analogs have potent oxytoxic effects and are used clinically for various stages of abortion and for cervical ripening.
Dinoprostone and carboprost tromethamine are synthetic analogs used for abortion and labor induction
Side effects include diarrhea, nausea, and vomiting, and vein irritation.

PGs in Semen

PGs may play a role in sperm transport in male and female reproductive tracts during and after coitus
Also assist in sperm nutrition through vasodilatation in genital mucosa.
PGs are absorbed by the genital mucosa, affecting fallopian tube motility and facilitating spermatozoa movement

PGE1 in Erectile Dysfunction

Used in treating impotence through intracavernous injections or urethral suppositories
Causes complete or partial erection; duration is 1–3 hours
Adverse effects include penile pain, prolonged erection (priapism), which can be reduced by careful dosaging

PGs and the Gastrointestinal Tract (GIT)

PGs primarily involve PGE and F series
PGs of A and E series inhibit histamine- and pentagastrin-induced gastric acid secretion without affecting mucosal blood flow
PGE compounds and their analogs protect against ulcers caused by steroids or NSAIDs
Misoprostol (PGE1 analog) and enprostil (PGE2 agonist) are cytoprotective at low doses and inhibit gastric secretion at high doses

PGs and the Respiratory Tract

Lung tissue contains PGF₂α and PGE₂
PGE₂ relaxes bronchial smooth muscle, counteracting bronchoconstriction induced by various stimuli, easing coughing and irritation
PGF₂α causes bronchial contraction, counteracting PGE2's bronchodilator effect
Bronchospasm in asthma might result from an imbalance between PGE₂ and PGF₂α.

Prostacyclin (PGI2)

Predominantly made in vascular endothelium and acts on IP receptors
Lowers peripheral and coronary resistance
Used for treating primary and secondary pulmonary hypertension (sometimes after mitral valve surgery)
Epoprostinol is a potent PGI2 analog; Treprostinil is given via continuous subcutaneous infusions

PGs and Cardiovascular (CV) Actions

PGEs reduce blood pressure by relaxing arteriolar smooth muscles, decreasing peripheral resistance
PGE₁ and PGE₂ are potent vasodilators
Limited CV response to PGs administered to induce abortion or labor induction.
PGI₂ also causes vasodilatation.
PGF series exhibit complex CV responses.

PG Uses in the Cardiovascular System

PGE and PGI₂ may be helpful in Raynaud's phenomenon and atherosclerosis
PGE₁ (alprostadil) may be utilized to maintain the patency of patent ductus arteriosus in congenital heart disease
COX inhibitors (e.g., indomethacin) can be used in cases of delayed closure of ductus arteriosus.
PGI₂ (epoprostenol) inhibits platelet aggregation during hemodialysis when heparin is contraindicated.

PGs and Renal Actions

PGs are released in the renal medulla in response to NA, angiotensin II, and sympathetic nerve stimulation.
Indomethacin (NSAID) inhibits this stimulation
PGE₂ and PGE₂ have diuretic and natriuretic actions
PGA₁ stimulates aldosterone release, leading to sodium retention
PGs are crucial for kidney autoregulation to maintain constant renal blood flow despite changes in blood pressure.

PGs in the Eye

PGE and PGF derivatives reduce intraocular pressure by increasing aqueous humor outflow via the uveoscleral pathway
Latonoprost, a derivative of PGF2α, is stable, long-acting, and topical, used to treat glaucoma
Bimatoprost, travoprost, and unoprostone similarly reduce intraocular pressure.

PGs and Bone Metabolism

PGs are produced by osteoblasts and nearby hematopoietic tissues.
PGE2, acting on EP4 receptors, stimulates bone resorption and formation.
PGs likely participate in bone changes and may contribute to bone loss during menopause due to inflammation.

PGs and Lipolysis

PGs, particularly PGE₂, counteract the lipolytic effects of cathecolamines and endocrine hormones like ACTH, TSH, and glucagon
This effect of PGs results in elevated fatty acid (FFA) levels in the blood.
PGs inhibit adenylate cyclase in adipose tissue

PGs and Body Temperature

Endotoxins induce the synthesis and release of PGs (especially PGE₁), stimulating temperature control centers to induce fever.
Antipyretic NSAIDs work by suppressing PG synthesis.

PGs and Inflammatory Reactions

PGs E1, E2, F1α, and F2 are released with other biologically active substances during inflammatory and hypersensitivity reactions.
Venoms from bees and some snakes also release PGs that mediate aspects of inflammation.
Phospholipase A2 also occurs in many venoms.

PG Metabolism

PGE and PGF activity is significantly reduced in the lung by PG-15-dehydrogenase in the blood and liver.
The enzyme modifies the 15-OH group to a corresponding keto group

Additional Metabolic Pathways

Metabolism may occur at C20 to yield a dicarboxylic acid.
Removal of two or more carbon units, with a variety of metabolic pathways and isomerases, may take place, such as PGA₁ to PGB₁ and PGA₂ to PGC₂.
Reduction of double bonds is a possible step.

Summary Table

Provides a summary of PGs, their primary effects, and the target systems. Table format. (Refer to the provided table images for specific details)

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Description

Explore the intriguing world of eicosanoids, which are lipid compounds crucial for various physiological functions in the body. This quiz covers their types, biosynthesis processes, and actions, highlighting their importance as local hormones. Gain a deeper understanding of their role in both human and plant biology.