Regulatory Functions Eicosanoids

Polyunsaturated fatty acids are precursors and intermediates of endogenous eicosanoid synthesis. The term eicosa-noids refers to hormone-like substances that exhibit a multitude of frequently antagonistic, mostly localized effects.

The major classes of prostaglandins are named PGA to PGI; an index indicates the number of C-C double-bonds outside of the ring (A). Prostaglandins with two double bonds, e. g., PGE2, are synthesized from arachidonic acid (20:4; n-6)—the other two double-bonds are lost during cyclization. Thromboxanes are related compounds with a six-mem-bered ether ring. Arachidonic acid can also be converted into leukotrienes by lipoxygenase. Leukotrienes were first discovered in leukocytes and have three conjugated double bonds. Prostagland-ins, thromboxanes, and leukotrienes are called eicosanoids since they have 20 (Greek: eikosi = 20) C-atoms.

Eicosanoid biosynthesis requires exogenous fatty acids of the n-6 and n-3 series from alimentary sources. The human body is unable to introduce a double bond between the 6th and 3rd C-atom, counting from the methyl end (the m-3 and m-6 positions). The body is able to elongate incoming fatty acids of these series at the carboxyl end and to further desaturate them (B); however, incoming higher level homologues remain n-6 and n-3 fatty acids. The most important precursor for the n-6 pathway is linoleic acid, which is present in most plant oils. It is designated as the essential fatty acid of this series, even though it can be replaced by the higher level homologues. Desaturation of C6 (counting from the carboxyl end) yields y-linolenic acid, which is rare in foods, with the exception of a few plant oils. Chain elongation by two C-atoms yields dihomo-y-linolenic acid, a direct precursor of several eicosanoids. Arachidonic acid, the main precursor substance for eicosanoid synthesis, can also be obtained from animal foods.

The n-3-pathway begins with a-lino-lenic acid, which is ubiquitous in very small amounts. Larger amounts are found, for example, in flaxseed oil and to a lesser extent in canola and soy oil. Higher level homologues are abundant in fish oils.

Desaturation and elongation of fatty acids of both series are catalyzed by identical enzymes. Due to this, two substances with varying degrees of affinity compete for the enzyme at any step. Hence, the equilibrium between the various eicosanoids can be influenced by dietary supply of specific, metaboliz-able intermediates. Exogenous fatty acids of this series from alimentary sources cannot be used directly for eicosanoid synthesis, however, regardless of their position in the synthesis pathway. They may be stored long term in fatty tissues or are inserted into phospholipids (at C2), which are used for cell membranes. From there they can be released by phospholipase A2, if needed. Hence, the cell membrane constitutes an available pool of fatty acids, the composition of which also has an impact on which eicosanoids are made.

Regulatory Functions II

  • A. Eicosanoid Synthesis
  • Oxidation

Elongation

Tissue triglycerides ^Cholesterol esters Phospholipids

ß-Oxidation

Series 1 eicosanoids Series 3 leukotrienes

Elongation

Tissue triglycerides ^Cholesterol esters Phospholipids

ß-Oxidation

Enerqy qain

ß-Oxidation

Enerqy qain

Desaturation

Membrane

22:6n-3 Docosahexaenoic acid

B. Arachidonic Acid Metabolism

A 6 Desaturation

Elongation

A5 Desaturation

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