Coronaric acid (leukotoxin or leukotoxin A) is a mono-unsaturated,

epoxide In organic chemistry, an epoxide is a cyclic ether, where the ether forms a three-atom ring: two atoms of carbon and one atom of oxygen. This triangular structure has substantial ring strain, making epoxides highly reactive, more so than other ...

derivative of the di-unsaturated fatty acid,

linoleic acid Linoleic acid (LA) is an organic compound with the formula . Both alkene groups () are ''cis''. It is a fatty acid sometimes denoted 18:2 (n−6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. Linoleic acid is a polyunsat ...

(i.e. 9(''Z''),12(''Z'') octadecadienoic acid). It is a mixture of the two optically active

isomers In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the existence or possibili ...

of 12(''Z'') 9,10-epoxy-octadecenoic acid. This mixture is also termed 9,10-epoxy-12Z-octadecenoic acid or 9(10)-EpOME (for Epoxy-Octadeca-MonoEnoic acid) and when formed by or studied in mammalians, leukotoxin.

Occurrence

Coronaric acid is found in the seed oils derived from plants in the

sunflower The common sunflower (''Helianthus annuus'') is a species of large annual forb of the daisy family Asteraceae. The common sunflower is harvested for its edible oily seeds, which are often eaten as a snack food. They are also used in the pr ...

family, such as ''Helianthus annuus'' and ''Xeranthemum annuum''. Coronaric acid is also formed by the cells and tissues of various mammalian (including human) species through the metabolism of linoleic acid by

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

(CYP)

epoxygenase Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 (CYP450 or just CYP) enzymes that metabolize polyunsaturated fatty acids (PUFAs) to epoxide products that have a range of biological activities. The most thoroughly-studi ...

enzymes. These CYPs (CYP2C9 and probably other CYPs that metabolize

polyunsaturated fatty acids In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...

to epoxides) metabolize linoleic acid to 9''S'',10''R''-epoxy-12(''Z'')-octadecenoic acid and 9''R'',10''S''-epoxy-12(''Z'')-octadecenoic acid, i.e. the (+) and (-) epoxy

optical isomers In chemistry, a molecule or ion is called chiral () if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality (). The terms are d ...

of coronaric acid. When studied in this context, the optical isomer mixture is often termed leukotoxin. These same CYP epoxygenases concurrently attack linoleic acid at the carbon 12,13 rather than 9,10

double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...

of linoleic acid to form a mixture of (+) and (-) epoxy

viz., 12''S'',13''R''-epoxy-9(''Z'')-octadecenoic and 12''R'',13''S''-epoxy-9(''Z'')-octadecenoic acids. This (+) and (-) optical mixture is often termed

vernolic acid Vernolic acid (leukotoxin B or isoleukotoxin) is a long chain fatty acid that is monounsaturated and contains an epoxide. It is a ''cis'' epoxide derived from the C12–C13 alkene of linoleic acid. Vernolic acid was first definitively character ...

when studied in plants and isoleukotoxin when studied in mammals. Coronaric acid is found in urine samples from healthy human subjects and increases 3- to 4-fold when these subjects are treated with a salt-loading diet. Coronaric and

s also form non-enzymatically when linoleic acid is exposed to oxygen and/or UV radiation as a result of the spontaneous process of

autoxidation Autoxidation (sometimes auto-oxidation) refers to oxidations brought about by reactions with oxygen at normal temperatures, without the intervention of flame or electric spark. The term is usually used to describe the gradual degradation of organi ...

. This autoxidation complicates studies in that it is often difficult to determine if these epoxy fatty acids identified in linoleic acid-rich plant and mammalian tissues represent actual tissue contents or are artifacts formed during their isolation and detection.

Metabolism

In mammalian tissue, coronaric acid is metabolized to its two corresponding dihydroxy

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

s, 9''S'',10''R''-dihydroxy-12(''Z'')-octadecenoic and 9''R'',10''S''-dihydroxy-12(''Z'')-octadecenoic acids, by

soluble epoxide hydrolase Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that in humans is encoded by the ''EPHX2'' gene. sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes, binds to specific epoxides and con ...

within minutes of its formation. The metabolism of coronaric acid to these two products, collectively termed leukotoxin diols, appears to be critical to coronaric acid's toxicity, i.e. the diols are the toxic metabolites of the non-toxic or far less toxic coronaric acid.

Activities

Toxicities

At very high concentrations, the linoleic acid-derived set of optical isomers, coronaric acid (i.e. leukotoxin) possesses toxicity similar to that of other structurally unrelated leukotoxins. It is toxic to leukocytes and other cell types, and when injected into rodents produces multiple organ failure and respiratory distress. These effects appear to be due to its conversion to its dihydroxy counterparts, 9''S'',10''R''- and 9''R'',10''S''-dihydroxy-12(''Z'')-octadecenoic acids by soluble epoxide hydrolase. Some studies suggest, but have not yet proven, that isoleukotoxin, acting primarily if not exclusively through its dihydroxy counterparts, is responsible for or contributes to multiple organ failure, the

acute respiratory distress syndrome Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin co ...

, and certain other cataclysmic diseases in humans (see ). Vernolic acid (i.e. isoleukotoxin) shares a similar metabolic fate in being converted by soluble epoxide hydrolase to its dihydroxide counterparts, resulting in the toxic actions of those counterparts.

Other activities

At lower concentrations, isoleukotoxin and its dihydroxy counterparts can protect from the toxic actions cited above that occur at higher concentrations of isoleukotoxin and leukotoxin; they may also share with the epoxides of arachidonic acid, i.e. the epoxyeicosatreienoates (see

Epoxyeicosatrienoic acid The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of cytochrome P450 enzymes, termed cytochrome P450 epoxygenases. They are nonclassic e ...

s), anti-hypertension activities.

References

{{Reflist Fatty acids Epoxides