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The results of this study Indicate that when human VLDL or LDL Is prepared under conditions allowing oxidation, such oxidation renders the molecular complexes highly toxic to human skin flbroblasta growing In culture. The cytotoxicity can be predicted by assaying for the presence of thlobarbiturlc acld-reactlng substances on the lipoprotein. However, malondialdehyde, which reacts with thiobarblturlc acid and Is known to be Injurious to cells, was not cytotoxic In the same experimental system when dissolved In culture medium or covalently bound to non-toxic LDL. The toxic agent(s) on oxidized LDL Is(are) located In a llpld-extractable moiety. Since lipld peroxides and oxidized sterols can occur in vivo under various pathological conditions, the cytotoxicity of these llpoprotein-assoclated substances observed In vitro may be related to certain manifestations of these conditions. Under specific conditions, very low density lipoprotein (VLDL) has also been observed to be toxic to Received November 24, 1982; accepted February 14, 1983. cultured cells. Chan and Pollard 67 showed that VLDL fractions from rats in the late stage of pregnancy are toxic to tumorigenic and nontransformed cells. Gianturco et al. 8 showed decreased viability of bovine aortic endothelial cells exposed to VLDL from hypertriacylglycerolemic humans, and Arbogast et al. 9 found that porcine aortic endothelial cells died when exposed to VLDL from diabetic rat serum.In addition to the above reports of lipoprotein-related cell injury and death, there are a number of studies describing the inhibition of proliferation of various stimulated leukocyte populations by lipoproteins, principally VLDL and LDL. 10 " 14 Among these is the study by Schuh et al. 12 who found that LDL was inhibitory in stimulated lymphocyte populations only when there was evidence of LDL "autoxidation."The reports mentioned in the above paragraphs are evidence of a growing range of interests in the injurious effects of lipoproteins. Each of the above papers alludes to potential in vivo pathophysiological roles for these phenomena, since the lipoprotein concentrations involved are well within physiological limits.Our preliminary data 15 indicated that the cytotoxic phenomenon may be related to lipoprotein oxidation. The results of the present study indicate conclusively that oxidation renders LDL highly toxic to cultured skin fibroblasts in a concentration-dependent fashion. Our results also demonstrate that the toxic substance resides in the chloroform-methanol extractable fraction of the lipoprotein. Our measure of lipoprotein oxidation is in terms of the equivalents of

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