TY - JOUR
T1 - Effects of oxo and dihydro metabolites of 12-hydroxy-5,8,10,14-eicosatetraenoic acid on chemotaxis and cytosolic calcium levels in hum and neutrophils
AU - Powell, W. S.
AU - Hashefi, M.
AU - Falck, J. R.
AU - Chauhan, K.
AU - Rokach, J.
AU - Wang, S. S.
AU - Mills, E.
AU - MacLeod, R. J.
PY - 1995
Y1 - 1995
N2 - One of the pathways of metabolism of leukotriene B4 (LTB4) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) in leukocytes is oxidation of the 12-hydroxyl group, followed by reduction of the 10,11-double bond. In the case of 12R-HETE and 12S-HETE, this results in the formation of 12-oxo-ETE, 10,11-dihydro-12-oxo-ETE, and the 12R and 12S isomers of 10,11-dihydro-12-HETE (i.e., 12R-HETrE and 12S-HETrE). We investigated the effects of metabolites of 12-HETE formed by this pathway on cytosolic calcium levels and chemotaxis in human neutrophils. 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. 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. The effect of 12S-HETrE on calcium levels was blocked by preincubation of these cells with LTB4, suggesting that it acted by stimulating the LTB4 receptor. 12R-HETrE was about 20 times less potent than its 12S isomer in stimulating cytosolic calcium in neutrophils and was also less active as a chemotactic agent. Oxidation of the 12-hydroxyl group to an oxo group resulted in a further loss of biological activity. 12-Oxo-ETE, 8-trans-12-oxo-ETE, and 12-oxo-ETrE had only modest effects on cytosolic calcium levels at concentrations as high as 10 μM and did not display detectable chemotactic activity. However, 12-oxo-ETE and its 8-trans isomer inhibited calcium responses to LTB4 by about 40%. It is concluded that reduction of the 10,11-double bond of 12-HETE results in a slight loss of biological activity on neutrophils, whereas oxidation of the 12-hydroxyl group results in a considerably greater loss of activity.
AB - One of the pathways of metabolism of leukotriene B4 (LTB4) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) in leukocytes is oxidation of the 12-hydroxyl group, followed by reduction of the 10,11-double bond. In the case of 12R-HETE and 12S-HETE, this results in the formation of 12-oxo-ETE, 10,11-dihydro-12-oxo-ETE, and the 12R and 12S isomers of 10,11-dihydro-12-HETE (i.e., 12R-HETrE and 12S-HETrE). We investigated the effects of metabolites of 12-HETE formed by this pathway on cytosolic calcium levels and chemotaxis in human neutrophils. 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. 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. The effect of 12S-HETrE on calcium levels was blocked by preincubation of these cells with LTB4, suggesting that it acted by stimulating the LTB4 receptor. 12R-HETrE was about 20 times less potent than its 12S isomer in stimulating cytosolic calcium in neutrophils and was also less active as a chemotactic agent. Oxidation of the 12-hydroxyl group to an oxo group resulted in a further loss of biological activity. 12-Oxo-ETE, 8-trans-12-oxo-ETE, and 12-oxo-ETrE had only modest effects on cytosolic calcium levels at concentrations as high as 10 μM and did not display detectable chemotactic activity. However, 12-oxo-ETE and its 8-trans isomer inhibited calcium responses to LTB4 by about 40%. It is concluded that reduction of the 10,11-double bond of 12-HETE results in a slight loss of biological activity on neutrophils, whereas oxidation of the 12-hydroxyl group results in a considerably greater loss of activity.
KW - 12-Hydroxyeicosanoid dehydrogenase
KW - 12-oxo-ETE
KW - 12R-HETE
KW - 12S-HETE
KW - Dihydro-12-HETE
KW - Eicosanoids
KW - Leukotriene B
UR - http://www.scopus.com/inward/record.url?scp=0028855695&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028855695&partnerID=8YFLogxK
U2 - 10.1002/jlb.57.2.257
DO - 10.1002/jlb.57.2.257
M3 - Article
C2 - 7852839
AN - SCOPUS:0028855695
SN - 0741-5400
VL - 57
SP - 257
EP - 263
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 2
ER -