Disease relevance of C05356

• The leukotrienes, prominent mediators of immediate hypersensitivity and inflammation, are derived from the major product of leukocyte lipoxygenase activity, 5-HPETE [1].

High impact information on C05356

• Finally, we have demonstrated that TNF stimulates production of lipoxygenase metabolites in TA1 cells and that one of these, 5-HPETE, induces c-fos, but not c-jun [2].
• Here, we report that CLP can up-regulate and modulate 5LO activity [formation of 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HPETE)], 5(S)-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HETE), and 5(S)-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid (LTA(4)) in vitro [3].
• The apparent Km of 5-HPETE was determined to be approximately 7 microM for microsomal GST-II and 21 microM for microsomal GST-III [4].
• This compound, 14d (2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methox y]- 4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]-butanoic acid, L-699,333), inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50s of 22 nM, 7 nM and 3.8 microM, respectively) [5].
• We found that 5,6-EET, 20-HETE, and 5-HPETE each activated distinct Ca(2+)-permeant nonselective cation channels (NSCCs) in primary B cells [6].

Biological context of C05356

• In the present study, human leukocyte homogenate 100,000 X g supernatant was incubated with 100 microM octadeuterated arachidonic acid and exogenous 5-HPETE (0-80 microM), and the isotopic composition of LTA4 hydrolysis products was determined by gas chromatography-mass spectrometry [7].
• However, LTB4 evoked chemotaxis with a linear dose response from 10(-9) to 10(-7) moles/l and 5-HPETE and 5-HETE from 5 X 10(-8) to 5 X 10(-6) moles/l. At 10(-7) moles/l LTB4 was approximately 6 and 8 X more potent in chemotaxis than 5-HPETE and 5-HETE respectively [8].
• It is proposed that 5-HPETE production by 5-lipoxygenase and subsequent inhibition of neuronal Na+, K(+)-ATPase activity may be a mechansim for modulating synaptic transmission [9].
• In these cells the 5-HPETE undergoes a cyclization reaction leading to a 5(6)-epoxy(oxido)eicosatetraenoic acid or leukotriene A4 [10].
• Oxygen consumption by this lipoxygenase was strictly dependent upon Ca2+, ATP and 5-HPETE [11].

Anatomical context of C05356

• It appears that the intermediate 5-HPETE may be generated extracellularly but has to re-enter the intracellular space for further metabolization [12].
• On the basis of these data we conclude that the endogenous synthesis of LTB4 is not directly involved in the neutrophil aggregatory response to FMLP, although the hydroperoxy intermediate 5-HPETE may act to enhance the cellular response [13].
• Exogenously supplied 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid (5-HPETE) and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) reversed the inhibitory effect of AA861 on 14C-alkyl-acetyl GPC production in A23187-stimulated prelabeled macrophages [14].
• They also suggest that this binding of 5-LO to the cell membrane enhances the subsequent conversion from 5-HPETE to LTA4 [15].
• These results suggest that 5-lipoxygenase products, especially 5-HPETE and 5-HETE, may play an important role in alkyl-acetyl GPC production in rat peritoneal macrophages [14].

Associations of C05356 with other chemical compounds

• In conclusion, an effective modulator of the AA cascade for the treatment of asthma and other inflammatory diseases may require 5-LO inhibitory activity as well as LTD4 antagonism in order to limit the effects of LTB4, LTD4, and 5-HPETE [16].
• The inhibitory effects of 12-lipoxygenase products were not exhibited by the 5-lipoxygenase-derived products, leukotriene B4 and 5-HPETE [17].
• The results indicate that FMLP-evoked O-2 may be enhanced by 10(-8)-10(-7)M levels of a number of lipids, in addition to LTB4, including 5-HPETE, 5-HETE, 5,15-DiHPETE and by higher levels of other 15-series lipoxygenase products and arachidonic acid [18].
• Although the hydroperoxy derivative 5-HPETE also inhibited the response to LTB4, in the relatively narrow concentration range of 1-4 microM it stimulated FMLP-induced aggregation [13].
• Specific metabolites of each pathway, i.e. PGF2 alpha and 5-HPETE, are able to transcend the block and restore collagenase production, invasiveness in vitro and metastatic activity in vivo [19].

Gene context of C05356

• The yield of 5-HPETE was considerably greater when the mu Bondapak C18 column was used [20].

Analytical, diagnostic and therapeutic context of C05356

• Radiolabeled 5-HPETE was measured by a radio-TLC analyser after separation by thin layer chromatography (TLC) [21].

References