Eicosanoids and Their Functions

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)