4-hydroxy-2-octenal and 4-hydroxy-2-nonenal

Lipid peroxidation produces several toxic carbonyls, including biologically active aldehydes. In previous studies, we demonstrated that 4-hydroxynonenal (HNE), one of the major products of lipoperoxidation, inhibited growth and c-myc expression in K562 and HL-60 human leukemic cells. In this study, we compared the HNE effects with those of 4-hydroxyoctenal (HOE), 4-hydroxyundecenal (HUE; different lengths of the lipophilic tail), and the analogous aldehydes 2-trans-nonanal (lacking the OH group) and nonenal (lacking the OH group and the trans CC double bond), on HL-60 cell proliferation and c-myc expression. HUE and HOE inhibited growth and c-myc expression in a dose-dependent fashion, with an effectiveness comparable with that of HNE, whereas 2-nonenal and nonanal did not affect these parameters. Our results showed that different aldehydes produced from lipid peroxidation may contribute to growth inhibition by c-myc downregulation and that the molecular features involved seem to be the hydroxy group and the trans CC double bond.

Topics: Aldehydes; Blotting, Northern; Cell Division; Cell Line; Dose-Response Relationship, Drug; HL-60 Cells; Humans; Proto-Oncogene Proteins c-myc; Reverse Transcriptase Polymerase Chain Reaction; RNA; Time Factors

We have investigated the cytotoxic and chemotactic potencies of malondialdehyde (MDA), hexanal, 4-hydroxyhexenal (HHE), 4-hydroxynonenal (HNE) and 4-hydroxyoctenal (HOE), which are aldehydes found in oxidised low density lipoprotein (LDL), for human monocyte-macrophages. They were toxic in the following order: hexanal

Topics: Aldehydes; Chemotactic Factors; Cytotoxins; Humans; Lipoproteins, LDL; Macrophages; Malondialdehyde; Monocytes; Oxidation-Reduction

A comparison has been made between the effects of 4-hydroxy-2,3-trans-nonenal (HNE) and 4-hydroxy-2,3-trans-octenal (HOE), two lipid peroxidation products, on the basal and GTPgammaS-stimulated activities of phosphoinositide-specific phospholipase C (PL-C) of rat polymorphonuclear leukocytes. PL-C activity was determined in vitro by measuring the hydrolysis of [3H] phosphatidylinositol-4,5-bis- phosphate (PtdIns-P2) added as exogenous substrate to neutrophil plasma membranes. PL-C was activated by concentrations of HNE ranging from 10(-8) to 10(-6) M both in the presence and in the absence of 2 x 10(-5) M GTPgammaS; HOE stimulated the enzymatic activity between 10(-11) and 10(-8) M; maximal stimulation was given by 10(-11) M HOE plus GTPgammaS. The aldehyde concentrations able to accelerate PtdIns-P2 breakdown displayed a good correspondence with those which have been reported to stimulate the oriented migration of rat neutrophils. Pretreatment of neutrophils with pertussis toxin prevented the stimulation of PL-C by 10(-11) M HOE and by HOE plus GTPgammaS. Our results suggest that the chemotactic action of HNE and HOE might depend on the activation of PL-C; furthermore a regulatory G protein appears to be involved in the acceleration of PtdIns-P2 turnover by HOE.

Topics: Aldehydes; Animals; Enzyme Activation; Guanosine Triphosphate; Neutrophils; Pertussis Toxin; Phosphatidylinositol Diacylglycerol-Lyase; Phosphoric Diester Hydrolases; Rats; Virulence Factors, Bordetella

4-Hydroxynonenal (HNE), a major lipid peroxidation product, displays several biological actions. Among them, the differentiation of human HL-60 cells and the stimulation of neutrophil oriented migration occur at concentrations which can be actually found in normal tissues and in body fluids. In spite of its chemotactic activity, HNE fails to increase neutrophil oxidative metabolism. The action of the aldehyde on cell migration appears to be mediated by a phosphoinositide specific phospholipase C. The acceleration of phosphatidylinositol turnover induced by 10 pM 4-hydroxyoctenal, another lipid peroxidation product, is prevented by the pretreatment of neutrophils with pertussis toxin. The mechanism of action of these 4-hydroxyalkenals appears to follow pathways common to other chemoattractants, but some differences can be found too. In particular HNE seems unable to stimulate phospholipase D activity. The action of 4-hydroxyalkenals and other lipid peroxidation products on transmembrane signalling systems and on phospholipid metabolism might regulate several cell functions, such as motility, proliferation and differentiation.

Topics: Aldehydes; Animals; Guanosine Triphosphate; Humans; Kinetics; Leukemia, Promyelocytic, Acute; Lipid Peroxidation; Male; Neutrophils; Phosphatidylinositol Diacylglycerol-Lyase; Phosphoric Diester Hydrolases; Rats; Rats, Wistar; Tumor Cells, Cultured

The effects of some 4-hydroxyalkenals, carbonylic products of lipid peroxidation, on hepatic phosphatidylinositol-4,5-bisphosphate (PIP2)-phospholipase C (PL-C) activity were investigated. The enzymatic activity was assayed in vitro by measuring the hydrolysis of [3H]PIP2 added as exogenous substrate to liver membranes. 4-Hydroxyhexenal (HEE), 4-hydroxyoctenal (HOE) and 4-hydroxynonenal (HNE) were able to stimulate both the basal and the GTPgammaS induced PL-C activity, whereas 4-hydroxyundecenal was inactive. HOE was the most active compound, being able to accelerate PIP2 breakdown at concentrations between 10(-12) and 10(-6) M, while in the case of HEE the effective doses ranged from 10(-11) to 10(-7) M and from 10(-9) to 10(-6) M in the case of HNE. 4-Hydroxynonenal was able to increase also bombesin stimulated PL-C activity. As these aldehydes accelerated PIP2 breakdown at doses which can be actually reached in tissues, the effects shown in vitro are likely to occur in vivo.

Topics: Aldehydes; Animals; Glutathione; Lipid Peroxidation; Liver; Male; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphoinositide Phospholipase C; Phosphoric Diester Hydrolases; Rats; Rats, Inbred Strains; Type C Phospholipases

Previous results from our laboratory showed that in vitro 4-hydroxyoctenal, 4-hydroxynonenal (HNE) and 4-hydroxytetradecenal elicit a neutrophil chemotactic response in the presence of albumin. Data presented here indicate that other hydroxyalkenals (4-hydroxyundecenal and 4-hydroxy-pentadecenal) also exert a chemotactic attraction on rat pleural neutrophils. The different aldehydes tested show a wide activity-concentration range, the most powerful being 4-hydroxyoctenal. Unlike most chemoattractants, the hydroxyalkenals seem deprived of chemokinetic properties. The mechanism by which these compounds may act on granulocytes is analysed. Experiments investigating the deactivation phenomenon induced by HNE indicate that this aldehyde acts as a chemoattractant by triggering mechanisms different from N-formylmethionyl-leucyl-phenylalanine (fMLP). In fact, cells pre-incubated with this peptide fail to respond chemotactically to the same compound, but are still able to respond to HNE. Similarly, the preventive contact of neutrophils with HNE is unable to influence the chemotactic effect of fMLP.

Topics: Aldehydes; Alkenes; Animals; Chemotaxis, Leukocyte; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Rats; Rats, Inbred Strains