Cytotoxicity and genotoxicity of lipid-oxidation products

Abstract

The autoxidation of unsaturated lipids contained in oils, fats, and food and the endogenous oxidative degradation of membrane lipids by lipid peroxidation result in the formation of a very complex mixture of lipid hydroperoxides, chain-cleavage products, and polymeric material. Experimental animal studies and biochemical investigations lend support to the hypothesis that lipid-oxidation products, ingested with food or produced endogenously, represent a health risk. The oral toxicity of oxidized lipids is unexpectedly low. Chronic uptake of large amounts of such materials increases tumor frequency and incidence of atherosclerosis in animals. 4-Hydroxynonenal, a chain-cleavage product resulting from omega 6 fatty acids, disturbs gap-junction communications in cultured endothelial cells and induces several genotoxic effects in hepatocytes and lymphocytes. Although the concentrations of the aldehyde needed to produce these effects are in the range expected to occur in vivo, their pathological significance is far from clear. Recent findings strongly suggest that in vivo modification of low-density lipoprotein by certain lipid-peroxidation products (eg, 4-hydroxynonenal and malonaldehyde) renders this lipoprotein more atherogenic and causes foam-cell formation. Proteins modified by 4-hydroxynonenal and malonaldehyde were detected by immunological techniques in atherosclerotic lesions.

Oxidant and antioxidant status in vegetarians and fish eaters

“…Several studies support the hypothesis that lipid oxidation products ingested with food or produced endogenously represent a health risk (1). It is well established that free radicals and reactive oxygen species are continuously produced in vivo.…”

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

“…The concentration of HNE is markedly increased under conditions of oxidative stress [16][17][18][19][20][21][22]. The biologic significance of HNE was first recognized to be as a secondary toxicant that was responsible for the "action at a distance"-damage caused by free radicals [23,24] and as a biomarker of oxidative stress [25]. Now it is clear that HNE can function as a signaling molecule at physiological concentrations by activating various signal transduction pathways and inducing expression of many genes, including phase II and antioxidant genes [26].…”

Hepatic stellate cells are not subjected to oxidant stress during iron-induced fibrogenesis in rodents

“…The latter phenomenon might be particularly true for those species, such as aldehydes, which have a long half-life and can elict their effect far from the site of generation. 38 However, by using monospecific antisera to MDA-lysine adducts, which have been shown to be highly sensitive for the detection of aldehyde-protein adducts in livers of CCl 4 39 or iron-treated rats, 14,37 we did find a dramatic increase of specific signal, but this signal was confined to cells that accumulate iron, mainly nonparenchymal cells. 5,6 It might be argued that a minimal amount of low-molecular-weight iron-chelates and/or nanomolar amounts of aldehydes that escape immunochemical detections may accumulate within HSC and turn on specific genetic programs through an oxidant stress (in the case of iron) or by forming adducts with key cytoplasmic or nuclear proteins (in the case of aldehydes).…”