PRIMARY  PRODUCTS
OF
FATTY ACID OXIDATION

Autoxidation and photo-oxidation of monoene, diene and triene fatty acids give similar but not identical products as it is summarized below (see review: Porter NA et al. Lipids, 1995, 30, 277) . Owing to possible allylic rearrangements in the oxidation products, the use of their distribution pattern for the exploration of the oxidant system remains questionable.

Fatty acids may be autoxidized either in free form or combined into glycerolipids or glycolipids. Thus, oxidized triacylglycerol monomers include molecules containing different oxygenated groups, mainly hydroxy, keto, and epoxy, as well as short-chain fatty acyl and short-chain n-oxo fatty acyl groups as the main products (Chang SS et al., JOACS 1978, 55, 718; Velasco J et al., Eur J Lipid Sci Technol 2004, 106, 728). 
The identification of the products of fatty acid autoxidation often provides valuable mechanistic information on the extent of the peroxidative injury.

Oxidation of monoene lipids

Studies of the autoxidation of oleic acid process date back to 1943 (Farmer EH et al., J Chem Soc 1943, 119 and 541). These authors suggested the mechanism involved in the formation with near equal probability of a hydroperoxy group at positions 8, 9, 10 and 11 of oleic acid. The 8- and 11-hydroperoxides have a cis/trans ratio near 1, while the other products are mainly trans. Rearrangements may happen in which the peroxy group migrates across the allylic backbone, thus, a 11-trans hydroperoxide may derive from a 9-trans product. Details are found in Porter NA et al (Lipids 1995, 30, 277).

In contrast, photo-oxidation produces equal amounts of only two products, 9- and 10-hydroperoxides (double bond in D10t and D8t, respectively).

Oxidation of diene lipids

Linoleic acid gives only two autoxidation products in equivalent amount (9-OOH and 13-OOH). These two isomers can change from c,t to t,t structure with exchange of the hydroperoxide group from C9 to C13 or vice versa but keep the conjugated diene structure, thus, four major products are found. They are also able to produce cyclic peroxides by addition of singlet oxygen to their conjugated dienes.

Photo-oxidation generates a mixture of four derivatives (amounts from 16 to 35% of the total products) with the OOH radical on the 9, 10, 12 or 13 carbon atom (double bonds in 10t12c, 8t12c, 9c13t, and 9c11t, respectively), two of these containing a conjugated diene system (9- and 13-OOH).

Homolytic cleavage and enzymatic transformation of these hydroperoxides produce aldehydic fatty acid derivatives which have important biological properties in plants. 

Nitric oxide ( ^.NO) and ^.NO-derived reactive species react with fatty acids during autocatalytic oxidation reactions to yield nitrate derivatives which were proved to be also cell signaling molecules. Nitrolinoleate has been shown to be present in plasma and cell lipids and to have vasomotor activity. 

The hydroperoxides (and their distribution) produced from linolenic acid by autoxidation or photo-oxidation are given below:

In 1975, the formation of endoperoxides species by cyclisation of fatty acid hydroperoxides was reported (Porter NA et al., J Org Chem 1975, 40, 3614). Later, the characterization of several products containing a ring group specific of F-type prostaglandins led to the description of the F2-isoprostanes (Morrow JD et al., PNAS 1990, 87, 9383).

F2-isoprostanes are formed in situ in arachidonic acid-containing phospholipids, and then released in free form.
Although isoprostanes are thought to be formed only by a cyclooxygenase-independent mechanism, evidence was reported for an enzymatic formation.

New peroxidation products of eicosapentaenoic acid, F3-isoprostanes, were shown to be formed in vitro (Nourooz-Zadeh J et al., Biochem Biophys Res Commun 1997, 236, 467). Later, several regioisomers, designated as 5-, 8-, 11-, 12-, 15-, and 18-series F3-Isoprostanes (F3-Isop) were shown to be formed in significant amounts in vitro and in vivo from the free radical-catalyzed peroxidation of eicosapentaenoic acid (Gao L et al., J Biol Chem 2006, 281, 14092). It was observed a relative abundance of 5- and 18-series F3-IsoPs over the other series.

In 2002 new arachidonic acid peroxidation products were discovered and as they are related biosynthetically to the isoprostanes and chemically characterized by a substituted tetrahydrofuran ring structure, they were named isofurans (Fessel JP et al., PNAS 2002, 99, 16713). There are formed by a free radical mechanism independent of the cyclooxygenase pathway.

It was shown that they are produced in vivo by a free radical mechanism independent of the cyclooxygenase pathway. These molecules are of interest as they provide a sensitive index of free-radical peroxidation under conditions of elevated oxygen tension where the production of isoprostanes appears to be limited. Their molecular structure suggests that 256 enantiomerically-pure isofurans may be formed. Thus, a nomenclature system was proposed to differentiate all the possible structures (Taber DF et al., Prost Lipid Med 2004, 73, 47). As increased levels of isofurans were detected in brain tissue of patients affected by several neural diseases, the determination of these molecules may be of value in appreciating oxidative damages to brain tissue (Fessel JP et al., J Neurochem 2003, 85, 645).
Neurofurans are an analogous family of compounds formed in vivo and in vitro from the free radical-initiated peroxidation of DHA (Song WL et al., J Biol Chem 2008, 283, 6). Sixteen regioisomers have been described by in vitro lipid peroxidation. One of them is shown below.

one representative neurofuran

 The levels of these compounds were elevated in the brain cortex of a mouse Alzheimer disease. Thus, neurofurans may prove useful in diagnosis of neurodegenerative diseases.

Several autoxidation products of eicosapentaenoic acid (EPA, 20:5 n-3) have been identified in vitro and in vivo (Yin H et al., J Biol Chem 2007, 282, 29890). Based on the free radical mechanism of arachidonic acid autoxidation, height regioisomeric hydroperoxydes can be generated. These products can be further oxidized to generate several monocyclic peroxides, serial cyclic peroxides, bicyclic endoperoxides and dioxolane-endoperoxides. 

It was shown that the oxidation of docosahexaenoic acid (DHA, 22:6 n-3) led to the formation of F2-isoprostane-like compounds which were named F4-neuroprostanes (NeuroP) (Roberts LJ et al., J Biol Chem 1998, 273, 13605). Their generation was described to result from DHA radicals, which forms eight F-ring neuroprostane regioisomers, following addition of molecular oxygen, endocyclization, another oxygen addition and reduction.

A facile nomenclature was proposed to allow the rational differentiation of each of the isomeric structures comprising the families of the neuroprostanes (Taber DF et al., Prost Lipid Med 2005, 78, 14). This nomenclature follows standard chemistry rules and conforms to prostaglandin conventions.
As these oxidation products were detected in patients with Alzheimer's disease at levels higher than control subjects, they may provide a unique marker of oxidative injury to the nervous system.

Free radical processes mediated by NO₂ were shown to generate a new family of arachidonic acid trans-isomers which are biologically active.