Toxicity of Polyunsaturated Fatty Acid Esters for Human Monocyte-Macrophages: The Anomalous Behaviour of Cholesteryl Linolenate

We have investigated the toxicity to human monocyte-macrophages, and susceptibility to oxidation, of different individual dietary fatty acids in cholesterol esters and triglycerides, added to the cell cultures as coacer-vates with bovine serum albumin. Toxicity was assessed using release of radioactivity from cells preloaded with tritiated adenine. Lipid oxidation was measured by gas chromatography (GC). The triglycerides showed a direct relationship between toxicity and increasing unsaturation, which in turn correlated with increasing susceptibility to oxidation. Triolein (18:l; μ-9) and trilinolein (18:2; μ-6) were non-toxic. Trilinolenin (18:3; μ-3) was toxic only after prolonged incubation. Triarachidonin (20:4; μ-6), trie-icosapentaenoin (20:5; μ-3) and tridocosahexaenoin (22:6; μ-3) were profoundly and rapidly toxic. There was a similar relationship between toxicity and increasing unsaturation for most of the cholesterol esters, but cholesteryl linolenate was apparently anomalous, being non-toxic in spite of possessing three double bonds and being extensively oxidised. Probucol and DL-α-tocopherol conferred protection against the toxicity of cholesteryl arachidonate and triarachidonin. The oxidation in these experiments was largely independent of the presence of cells. GC indicated that formation of 7-oxysterols might contribute to the toxicity of cholesteryl linoleate. The toxicity of triglycerides suggests that polyunsaturated fatty acid peroxidation products are also toxic. Possible mechanisms of cyto-toxicity and relevance to atherosclerosis are discussed.