Abstract
The objective of this study was to determine the effect of 2,2-diphenyl-5-(4-{[(1E)-pyridin-3-yl-methylidene]-amino}piperazin-1-yl)pentanenitrile (SC-26196), a Δ6-desaturase inhibitor, on PUFA metabolism in human cells. SC-26196 inhibited the desaturation of 2 μM [1-14C] 18∶2n−6 by 87–95% in cultured human skin fibroblasts, coronary artery smooth muscle cells, and astrocytes. By contrast, SC-26196 did not affect the conversion of [1-14C]20∶3n−6 to 20∶4 in the fibroblasts, demonstrating that it is selective for Δ6-desaturase. The IC50 values for inhibition of the desaturation of 2 μM [1-14C] 18∶3n−3 and [3-14C]24∶5n−3 in the fibroblasts, 0.2–0.4 μM, were similar to those for the inhibition of [1-14C] 18∶2n−6 desaturation, and the rates of recovery of [1-14C] 18∶2n−6 and [3-14C] 24∶5n−3 desaturation after removal of SC-26196 from the culture medium also were similar. SC-26196 reduced the conversion of [3-14C] 22∶5n−3 and [3-14C] 24∶5n−3 to DHA by 75 and 84%, respectively, but it had no effect on the retroconversion of [3-14C] 24∶6n−3 to DHA. These results demonstrate that SC-26196 effectively inhibits the desaturation of 18- and 24-carbon PUFA and, therefore, decreases the synthesis of arachidonic acid, EPA, and DHA in human cells. Furthermore, they provide additional evidence that the conversion of 22∶5n−3 to DHA involves Δ6-desaturation.
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Abbreviations
- AM:
-
acetoxymethyl ester
- BME:
-
basal medium Eagle
- FADS:
-
fatty acid desaturase
- HSF:
-
human skin fibroblasts
- MEM:
-
minimum essential medium
- SC-26196:
-
2,2-diphenyl-5-(4-{[(1E)-pyridin-3-yl-methylidene]amino}piperazin-1-yl)pentanenitrile
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Harmon, S.D., Kaduce, T.L., Manuel, T.D. et al. Effect of the Δ6-desaturase inhibitor SC-26196 on PUFA metabolism in human cellsinhibitor SC-26196 on PUFA metabolism in human cells. Lipids 38, 469–476 (2003). https://doi.org/10.1007/s11745-003-1086-9
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DOI: https://doi.org/10.1007/s11745-003-1086-9