J. Lipid Res.
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A more recent version of this article appeared on November 1, 2006

Papers In Press, published online ahead of print August 9, 2006
J. Lipid Res., doi:10.1194/jlr.M600280-JLR200
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Submitted on June 28, 2006
Revised on August 2, 2006
Accepted on August 9, 2006

Dihydroxydocosahexaenoic acids of the neuroprotectin D family: Synthesis, structure and inhibition of human 5-lipoxygenase

Igor A. Butovich, Svetlana M. Lukyanova, and Carl Bachmann

Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9057

Corresponding Author: igor.butovich{at}utsouthwestern.edu

During aerobic oxidation of docosahexaenoic acid (DHA), soybean lipoxygenase (sLOX) has been shown to form 7,17(S)-dihydro(pero)xy-DHA [7,17(S)-diH(P)DHA] along with its previously described positional isomer 10,17(S)-diH(P)DHA (I. Butovich, 2006, J. Lipid Res. 47, 861-870). 7,17(S)-diH(P)DHA was also obtained via sLOX-catalyzed oxidation of either 17(S)-hydroperoxy-DHA [17(S)-HPDHA] or 17(S)-hydroxy-DHA [17(S)-HDHA]. The structures of the products were elucidated by normal phase, reversed phase, and chiral phase HPLC analyses and by UV, NMR, MS/MS spectroscopies, and GC-MS. 7,17(S)-diH(P)DHA was shown to have 4Z,8E,10Z,13Z,15E,19Z geometry of the double bonds. In addition, a compound apparently identical to the sLOX-derived 7,17(S)-diH(P)DHA was produced by another enzyme, potato tuber LOX, in the reactions of oxygenation of either 17(S)-HPDHA or 17(S)-HDHA. All the diHDHAs formed by either of the enzymes were clearly produced through double lipoxygenation of the corresponding substrate. 7,17(S)-diHDHA inhibited human recombinant 5LOX (hr5LOX) in the reaction of arachidonic acid (AA) oxidation. In standard conditions with 100mu M AA as substrate, the IC50 value for 7,17(S)-diHDHA was found to be 7mu M, while IC50 for 10,17(S)-DiHDHA was 15mu M. Similar inhibition by the diHDHAs was observed with sLOX – a quintessential 15LOX – though the strongest inhibition was produced by 10,17(S)-diHDHA (IC50 4mu M). Inhibition of sLOX by 7,17(S)-diHDHA was slightly less potent with IC50 value of 9mu M. These findings suggest that 7,17(S)-diHDHA along with its 10,17(S)-counterpart might have anti-inflammatory and anti-cancer activities, which could be exerted, at least in part, through direct inhibition of 5LOX and 15LOX.


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I. A. Butovich and S. M. Lukyanova
Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies
J. Lipid Res., June 1, 2008; 49(6): 1284 - 1294.
[Abstract] [Full Text] [PDF]


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