LOVASTATIN INCREASES ARACHIDONIC-ACID LEVELS AND STIMULATES THROMBOXANE SYNTHESIS IN HUMAN LIVER AND MONOCYTIC CELL-LINES

The effect of lovastatin (LOV), the inhibitor of 3-hydroxy-3-methyl-gl utaryl coenzyme A reductase, on linoleic acid (LA, 18:2n-6) metabolism was examined in human monocytic Mono Mac 6 (MM6) and hepatoma Hep G2 cells. The desaturation of LA was examined after LOV (72 h, 10 mu M) o r dimethylsulfoxide (LOV carrier, < 0.1%) and [C-14]LA (last 18 h, 0.3 mu Ci, 5 mu M). In both cell lines, LOV reduced the percentage of C-1 4 label associated with LA and increased the percentage of label in th e 20:4n-6 and the 22:5n-6 fractions. In Hep G2 but not MM6 cells, this effect was fully reversible by means of coincubation with mevalonic a cid (500 mu M), but not with cholesterol or lipoproteins. In both cell lines, the LOV-mediated increase in LA desaturation resulted in dose- dependent reductions of LA and elevations of AA in cellular phospholip ids. The lipids secreted by LOV-treated Hep G2 cells were also enriche d in arachidonic acid (AA). In the MM6 cells, LOV increased release of thromboxane upon stimulation with the calcium ionophore A23187. In su mmary, our findings of higher LA desaturation and AA enrichment of lip ids secreted by the Hep G2 cells suggest that LOV treatment may increa se the delivery of AA from the liver to extrahepatic tissues. The chan ges in membrane fatty acid composition can influence a variety of cell ular functions, such as eicosanoid synthesis in monocytic cells. The m echanism appears to be related to the reduced availability of intermed iates of cholesterogenesis.