Coronaric acid (isoleukotoxin) is a mono-unsaturated,

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...

derivative of the di-saturated fatty acid,

linoleic acid Linoleic acid (LA) is an organic compound with the formula COOH(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are cis-trans isomerism, ''cis''. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 ''cis''-9,12. A linoleate is a salt (chem ...

(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 formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...

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

Occurrence

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

sunflower The common sunflower (''Helianthus annuus'') is a large annual forb of the genus ''Helianthus'' grown as a crop for its edible oily seeds. Apart from cooking oil production, it is also used as livestock forage (as a meal or a silage plant), as ...

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

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

(CYP)

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

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

polyunsaturated fatty acids Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...

to epoxides) metabolize linoleic acid to (+)12''S'',13''R''-epoxy-9(''Z'')-octadecaenoic acid and (-)12''R'',13''S''-epoxy-9(''Z'')-octadecaenoic acid, i.e. the (+) and (-) epoxy optical isomers of coronaric acid. When studied in this context, the optical isomer mixture is often termed isoleukotoxin. This same CYP epoxygenases concurrently attack linoleic acid at the carbon 9,10 rather than 12,13

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 optical isomers viz., 9''S'',10''R''-epoxy-12(''Z'')-octadecaenoic and 9''R'',10''S''-epoxy-12(''Z'')-octadecaenoic acids. This (+) and (-) optical mixture is often termed

vernolic acid Vernolic acid (leukotoxin) is a long chain fatty acid that is monounsaturated and contains an epoxide. It is the R,R-''cis'' epoxide derived from the C12–C13 alkene of linoleic acid. Vernolic acid was first definitively characterized in 1954. I ...

or when studied in plants and leukotoxin when studied in mammals. Coronoric 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 vernolic acids also form non-enzymatically when linoleic acid is exposed to oxygen and/or UV radiation as a result of the spontaneous process of

autooxidation 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, 12''S'',13''R''-dihydroxy-9(''Z'')-octadecaenoic and 12''R'',13''S''-dihydroxy-9(''Z'')-octadecaenoic 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 convert ...

within minutes of its formation. The metabolism of coronaric acid to these two products, collectively termed isoleukotoxin 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. isoleukotoxin), possesses activities similar to that of other structurally unrelated leukotoxins viz., It is toxic to leukocytes and other cell types and when injected into rodents produce multiple organ failure and respiratory distress. These effects appear due to its conversion to its dihydroxy counterparts, 9''S'',10''R''- and 9''R'',10''S''-dihydroxy-12(''Z'')-octadecaenoic 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 contribute 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 colo ...

, and certain other cataclysmic diseases in humans (see

section on linoleic acid). Vernolic acid (i.e. leukotoxin) shares a similar metabolic fate in being converted by soluble epoxide hydrolase to its dihydroxide counterparts and toxic actions of these hydroxide 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 acids), anti-hypertension activities.

References

{{Reflist Fatty acids Epoxides