Coronaric acid#toxicity

Coronaric acid is found in the seed oils derived from plants in the sunflower family, such as Helianthus annuus{{cite journal | pmid = 17805802 | year = 1968 | last1 = Mikolajczak | first1 = K. L. | title = Oxygenated fatty acids of oil from sunflower seeds after prolonged storage | journal = Lipids | volume = 3 | issue = 6 | pages = 489–94 | last2 = Freidinger | first2 = R. M. | last3 = Smith Jr | first3 = C. R. | last4 = Wolff | first4 = I. A. | doi = 10.1007/BF02530891 | s2cid = 4028426 }} and Xeranthemum annuum.{{cite journal | pmid = 17805745 | year = 1967 | last1 = Powell | first1 = R. G. | title = Cis-5,cis-9,cis-12-octadecatrienoic and some unusual oxygenated acids in Xeranthemum annuum seed oil | journal = Lipids | volume = 2 | issue = 2 | pages = 172–7 | last2 = Smith Jr | first2 = C. R. | last3 = Wolff | first3 = I. A. | doi = 10.1007/BF02530918 | s2cid = 3994480 }}

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 (CYP) epoxygenase enzymes. These CYPs (CYP2C9 and probably other CYPs that metabolize polyunsaturated fatty acids to epoxides) metabolize linoleic acid to 9S,10R-epoxy-12(Z)-octadecenoic acid and 9R,10S-epoxy-12(Z)-octadecenoic acid, i.e. the (+) and (-) epoxy optical isomers of coronaric acid.{{cite journal | pmid = 10729206 | year = 2000 | last1 = Draper | first1 = A. J. | title = Identification of CYP2C9 as a human liver microsomal linoleic acid epoxygenase | journal = Archives of Biochemistry and Biophysics | volume = 376 | issue = 1 | pages = 199–205 | last2 = Hammock | first2 = B. D. | doi = 10.1006/abbi.2000.1705 | s2cid = 21213904 | url = http://pdfs.semanticscholar.org/6490/0a43db8faa97b022f3129bef349c7d6bb2bb.pdf | archive-url = https://web.archive.org/web/20200101192417/http://pdfs.semanticscholar.org/6490/0a43db8faa97b022f3129bef349c7d6bb2bb.pdf | url-status = dead | archive-date = 2020-01-01 }}{{cite journal | pmid = 20869469 | year = 2011 | last1 = Konkel | first1 = A. | title = Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1814 | issue = 1 | pages = 210–22 | last2 = Schunck | first2 = W. H. | doi = 10.1016/j.bbapap.2010.09.009 }}{{cite journal | pmid = 25093613 | pmc = 4314516 | year = 2015 | last1 = Spector | first1 = A. A. | title = Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 4 | pages = 356–65 | last2 = Kim | first2 = H. Y. | doi = 10.1016/j.bbalip.2014.07.020 }} 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 of linoleic acid to form a mixture of (+) and (-) epoxy optical isomers viz., 12S,13R-epoxy-9(Z)-octadecenoic and 12R,13S-epoxy-9(Z)-octadecenoic acids. This (+) and (-) optical mixture is often termed vernolic acid 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 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 autoxidation.{{cite journal | pmid = 481136 | year = 1979 | last1 = Sevanian | first1 = A | title = Epoxides as products of lipid autoxidation in rat lungs | journal = Lipids | volume = 14 | issue = 7 | pages = 634–43 | last2 = Mead | first2 = J. F. | last3 = Stein | first3 = R. A. | doi=10.1007/bf02533449| s2cid = 4036806 }} 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.

In mammalian tissue, coronaric acid is metabolized to its two corresponding dihydroxy stereoisomers, 9S,10R-dihydroxy-12(Z)-octadecenoic and 9R,10S-dihydroxy-12(Z)-octadecenoic acids, by soluble epoxide hydrolase within minutes of its formation.{{cite journal | pmid = 10775319 | year = 2000 | last1 = Greene | first1 = J. F. | title = Toxicity of epoxy fatty acids and related compounds to cells expressing human soluble epoxide hydrolase | journal = Chemical Research in Toxicology | volume = 13 | issue = 4 | pages = 217–26 | last2 = Newman | first2 = J. W. | last3 = Williamson | first3 = K. C. | last4 = Hammock | first4 = B. D. | doi=10.1021/tx990162c}} 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.

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.{{cite journal | pmid = 9299596 | year = 1997 | last1 = Moran | first1 = J. H. | title = Cytotoxicity of linoleic acid diols to renal proximal tubular cells | journal = Toxicology and Applied Pharmacology | volume = 146 | issue = 1 | pages = 53–9 | last2 = Weise | first2 = R | last3 = Schnellmann | first3 = R. G. | last4 = Freeman | first4 = J. P. | last5 = Grant | first5 = D. F. | doi = 10.1006/taap.1997.8197 | bibcode = 1997ToxAP.146...53M | url = https://zenodo.org/record/1229968 }}{{cite book | pmid = 10667370 | year = 1999 | last1 = Greene | first1 = J. F. | volume = 469 | pages = 471–7 | last2 = Hammock | first2 = B. D. | title = Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 4 | chapter = Toxicity of Linoleic Acid Metabolites | series = Advances in Experimental Medicine and Biology | doi = 10.1007/978-1-4615-4793-8_69 | isbn = 978-1-4613-7171-7 }}{{cite journal | pmid = 20528947 | pmc = 3034196 | year = 2010 | last1 = Linhartová | first1 = I. | title = RTX proteins: A highly diverse family secreted by a common mechanism | journal = FEMS Microbiology Reviews | volume = 34 | issue = 6 | pages = 1076–112 | last2 = Bumba | first2 = L. | last3 = Mašín | first3 = J. | last4 = Basler | first4 = M. | last5 = Osička | first5 = R. | last6 = Kamanová | first6 = J. | last7 = Procházková | first7 = K. | last8 = Adkins | first8 = I. | last9 = Hejnová-Holubová | first9 = J. | last10 = Sadílková | first10 = L. | last11 = Morová | first11 = J. | last12 = Sebo | first12 = P. | doi = 10.1111/j.1574-6976.2010.00231.x }} These effects appear to be due to its conversion to its dihydroxy counterparts, 9S,10R- and 9R,10S-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, and certain other cataclysmic diseases in humans (see {{slink|Epoxygenase|Linoleic acid}}).{{cite journal | pmid = 11694448 | year = 2001 | last1 = Zheng | first1 = J. | title = Leukotoxin-diol: A putative toxic mediator involved in acute respiratory distress syndrome | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 25 | issue = 4 | pages = 434–8 | last2 = Plopper | first2 = C. G. | last3 = Lakritz | first3 = J. | last4 = Storms | first4 = D. H. | last5 = Hammock | first5 = B. D. | doi = 10.1165/ajrcmb.25.4.4104 | s2cid = 27194509 }} 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.

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.

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Category:Fatty acids

Category:Epoxides