Effect of the Δ6‐desaturase inhibitor SC‐26196 on PUFA metabolism in human cellsinhibitor SC‐26196 on PUFA metabolism in human cells

Abstract The objective of this study was to determine the effect of 2,2‐diphenyl‐5‐(4‐{[(1 E )‐pyridin‐3‐yl‐methylidene]‐amino}piperazin‐1‐yl)pentanenitrile (SC‐26196), a Δ 6 ‐desaturase inhibitor, on PUFA metabolism in human cells. SC‐26196 inhibited the desaturation of 2 μM [1‐ 14 C] 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‐ 14 C]20∶3n−6 to 20∶4 in the fibroblasts, demonstrating that it is selective for Δ 6 ‐desaturase. The IC 50 values for inhibition of the desaturation of 2 μM [1‐ 14 C] 18∶3n−3 and [3‐ 14 C]24∶5n−3 in the fibroblasts, 0.2–0.4 μM, were similar to those for the inhibition of [1‐ 14 C] 18∶2n−6 desaturation, and the rates of recovery of [1‐ 14 C] 18∶2n−6 and [3‐ 14 C] 24∶5n−3 desaturation after removal of SC‐26196 from the culture medium also were similar. SC‐26196 reduced the conversion of [3‐ 14 C] 22∶5n−3 and [3‐ 14 C] 24∶5n−3 to DHA by 75 and 84%, respectively, but it had no effect on the retroconversion of [3‐ 14 C] 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 Δ 6 ‐desaturation.