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Chemical Compound Review

CHEMBL1435825     (5Z,8Z,10E,12R,14Z)-12- hydroxyicosa-5,8,10...

Synonyms: BSPBio_001297, CHEBI:34144, BML1-B08, LMFA03060008, HMS1361A19, ...
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Disease relevance of 12R-HETE

  • A recognized feature of psoriasis and other proliferative dermatoses is accumulation in the skin of the unusual arachidonic acid metabolite, 12R-hydroxyeicosatetraenoic acid (12R-HETE) [1].
  • The ability of 12(R)-HETE and 12(R)-DH-HETE to mediate the clinical signs of corneal hypoxia suggest these metabolites may be potential mediators of contact lens complications that followed conditions of hypoxic stress and possibly mechanical irritation in this model [2].
  • The levels of 15(S)-HETE and 12(R)-HETE had a 125- to 144-fold range and were highest in scales from a patient with erythroderma and in three psoriatic scale samples similarly analyzed [3].
  • These results suggest that one of the effects of copper ion on the corneal neovascularization may be to regulate the level of 12(R)-HETE [4].
  • Psoriasis is a disease state characterized by epidermal proliferation, neutrophil infiltration, along with release of the proinflammatory mediators leukotriene-B4(LTB4) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] [5].

High impact information on 12R-HETE

  • Both mitochondrial and microsomal activities were increased upon addition of NADPH and were inhibited by carbon monoxide, but the molar ratio of 12S/12R-HETE was threefold greater in microsomal than in mitochondrial fractions [6].
  • Here we provide mechanistic evidence for a lipoxygenase route to 12R-HETE in human psoriatic tissue and describe a 12R-lipoxygenase that can account for the biosynthesis [1].
  • In parallel with these results both TPA and 12(S)-HETE [but not 12(R)-HETE] enhance tumor cell adhesion to endothelial cells, subendothelial matrix and fibronectin, but not to type IV collagen [7].
  • It was slightly less potent than 12R-HETE, consistent with the concept that reduction of the 10,11-double bond results in a loss of biological activity on neutrophils [8].
  • Of the above series of metabolites, 12S-HETrE (which has the same absolute stereochemistry at C-12 as 12R-HETE) was the most potent in stimulating both cytosolic calcium levels and chemotaxis [8].

Chemical compound and disease context of 12R-HETE


Biological context of 12R-HETE


Anatomical context of 12R-HETE

  • The corneal epithelium metabolizes arachidonic acid by a cytochrome P450-(CYP) mediated pathway to 12(R)hydroxy-5,8,10,14-eicosatrienoic acid [12(R)-HETE] and 12(R)hydroxy-5,8,14-eicosatrienoic acid [12(R)-HETrE] [14].
  • These cultured corneas exhibit epithelial cytochrome P450 CYP-dependent 12(R)-HETE and 12(R)-HETrE synthesis as indicated by chiral analysis and by the ability of CYP enzyme inhibitors to repress their synthesis [14].
  • 2. 12(R)-HETE was shown to be chemotactic for lymphocytes over the range 5 x 10(-7) to 5 x 10(-5) M [15].
  • These results suggest that 12(R)-HETE synthesis by porcine ciliary microsomes may be mediated by a cytochrome P450 of the IA family [16].
  • Both basal and induced levels of 12(R)-HETE synthesizing activity were considerably higher in nonpigmented epithelial cells than in pigmented cells of the ciliary processes [16].

Associations of 12R-HETE with other chemical compounds


Gene context of 12R-HETE

  • CYP2C9 appeared to form 12R-HETE and 13-HETE, whereas CYP2C8 formed 13-HETE, 11-HETE and 15-HETE as main monohydroxy metabolites [19].
  • LTB4 and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase [17].
  • This effect is likely due to inhibition of cytochrome P450 and consequent reduction in levels of 12R-HETE in the skin [20].
  • 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] is present in large quantities in human psoriatic lesional skin and can be further metabolized by 5-LO to 5(S), 12(R)-dihydroxy-(6E,8Z,10E,14Z)-eicosatetraenoic acid (6-trans-LTB4) [21].
  • At doses up to 50 mu gm per intradermal site, 12(R)-HETE was chemoattractant to the neutrophil (as assessed by dermal myeloperoxidase levels) with response in the cavine greater than canine greater than lapine greater than mouse greater than rat [5].

Analytical, diagnostic and therapeutic context of 12R-HETE

  • We used a model of corneal organ culture that exhibits hypoxia-induced epithelial CYP-dependent 12(R)-HETE and 12(R)-HETrE synthesis for isolating, identifying, and characterizing the CYP protein responsible for these eicosanoid syntheses [22].


  1. A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression. Boeglin, W.E., Kim, R.B., Brash, A.R. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  2. Induction of corneal epithelial cytochrome P-450 arachidonate metabolism by contact lens wear. Davis, K.L., Conners, M.S., Dunn, M.W., Schwartzman, M.L. Invest. Ophthalmol. Vis. Sci. (1992) [Pubmed]
  3. Epidermal fatty acid oxygenases are activated in non-psoriatic dermatoses. Baer, A.N., Klaus, M.V., Green, F.A. J. Invest. Dermatol. (1995) [Pubmed]
  4. The effect of copper ion on arachidonic acid metabolism in the porcine corneal epithelium. Lin, M.T., Wang, Y.H., Chen, Y.L., Chang, W.C. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  5. 12(R)-hydroxyeicosatetraenoic acid is a neutrophil chemoattractant in the cavine, lapine, murine and canine dermis. Fretland, D.J., Widomski, D.L., Zemaitis, J.M., Tsai, B.S., Djuric, S.W., Penning, T.D., Miyashiro, J.M., Bauer, R.F. Prostaglandins Leukot. Essent. Fatty Acids (1989) [Pubmed]
  6. A regiospecific monooxygenase with novel stereopreference is the major pathway for arachidonic acid oxygenation in isolated epidermal cells. Holtzman, M.J., Turk, J., Pentland, A. J. Clin. Invest. (1989) [Pubmed]
  7. Bidirectional control of membrane expression and/or activation of the tumor cell IRGpIIb/IIIa receptor and tumor cell adhesion by lipoxygenase products of arachidonic acid and linoleic acid. Grossi, I.M., Fitzgerald, L.A., Umbarger, L.A., Nelson, K.K., Diglio, C.A., Taylor, J.D., Honn, K.V. Cancer Res. (1989) [Pubmed]
  8. Effects of oxo and dihydro metabolites of 12-hydroxy-5,8,10,14-eicosatetraenoic acid on chemotaxis and cytosolic calcium levels in human neutrophils. Powell, W.S., Hashefi, M., Falck, J.R., Chauhan, K., Rokach, J., Wang, S.S., Mills, E., MacLeod, R.J. J. Leukoc. Biol. (1995) [Pubmed]
  9. SC-41930 inhibits neutrophil infiltration of the cavine dermis induced by 12(R)-hydroxyeicosatetraenoic acid. Fretland, D.J., Widomski, D.L., Shone, R.L., Penning, T.D., Miyashiro, J.M., Djuric, S.W. Prostaglandins Leukot. Essent. Fatty Acids (1989) [Pubmed]
  10. Isomers of 12-hydroxy-5,8,10,14-eicosatetraenoic acid reduce renin activity and increase water and electrolyte excretion. Quilley, C.P., McGiff, J.C. J. Pharmacol. Exp. Ther. (1990) [Pubmed]
  11. Metabolism of arachidonic acid by isolated rabbit ciliary epithelium. King, K.L., Delamere, N.A., Csukas, S.C., Pierce, W.M. Exp. Eye Res. (1992) [Pubmed]
  12. Evidence for LTB4/12-HETE binding sites in a human epidermal cell line. Gross, E., Ruzicka, T., Mauch, C., Krieg, T. Prostaglandins (1988) [Pubmed]
  13. Effects of 12-HETE on isolated dog renal arcuate arteries. Ma, Y.H., Harder, D.R., Clark, J.E., Roman, R.J. Am. J. Physiol. (1991) [Pubmed]
  14. Hypoxia stimulates the synthesis of cytochrome P450-derived inflammatory eicosanoids in rabbit corneal epithelium. Vafeas, C., Mieyal, P.A., Urbano, F., Falck, J.R., Chauhan, K., Berman, M., Schwartzman, M.L. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  15. Contrasting in vitro lymphocyte chemotactic activity of the hydroxyl enantiomers of 12-hydroxy-5,8,10,14-eicosatetraenoic acid. Bacon, K.B., Camp, R.D., Cunningham, F.M., Woollard, P.M. Br. J. Pharmacol. (1988) [Pubmed]
  16. 12(R)-hydroxyeicosatetraenoic acid synthesis by 3-methylcholanthrene- and clofibrate-inducible cytochrome P450 in porcine ciliary epithelium. Asakura, T., Shichi, H. Biochem. Biophys. Res. Commun. (1992) [Pubmed]
  17. Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist, SC-53228: impact upon leukotriene B4- and 12(R)-HETE-mediated events. Fretland, D.J., Anglin, C.P., Bremer, M., Isakson, P., Widomski, D.L., Paulson, S.K., Docter, S.H., Djuric, S.W., Penning, T.D., Yu, S. Inflammation (1995) [Pubmed]
  18. Synthesis of 12(R)- and 12(S)-hydroxyeicosatetraenoic acid by porcine ocular tissues. Asakura, T., Matsuda, M., Matsuda, S., Shichi, H. Journal of ocular pharmacology. (1994) [Pubmed]
  19. Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes. Bylund, J., Kunz, T., Valmsen, K., Oliw, E.H. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  20. Novel 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols with topical antiinflammatory activity. Wright, S.W., Harris, R.R., Collins, R.J., Corbett, R.L., Green, A.M., Wadman, E.A., Batt, D.G. J. Med. Chem. (1992) [Pubmed]
  21. 6-trans-leukotriene B4 is a neutrophil chemotaxin in the guinea pig dermis. Fretland, D.J., Widomski, D.L., Anglin, C.P., Walsh, R.E., Levin, S., Gaginella, T.S. J. Leukoc. Biol. (1991) [Pubmed]
  22. Hypoxia-induced production of 12-hydroxyeicosanoids in the corneal epithelium: involvement of a cytochrome P-4504B1 isoform. Mastyugin, V., Aversa, E., Bonazzi, A., Vafaes, C., Mieyal, P., Schwartzman, M.L. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
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