[On the extensively selective in-vivo destruction of subcutaneously implanted Ehrlich ascites tumor cells using 4-hydroxy-enales, especially 4-hydroxy-pentenal].
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Absorption↗
Biomedical subjects
H Esterbauer
Publications and source records attributed to H Esterbauer.
Modification of human serum low density lipoprotein by oxidation--characterization and pathophysiological implications.
Plasma low density lipoprotein (LDL) can undergo free radical oxidation either catalyzed by divalent cations, such as Cu2+ or Fe2+ or promoted by incubation with cultured cells such as endothelial cells, smooth muscle cells and monocytes. The content of vitamin E, beta-carotene and unsaturated fatty acids is decreased in oxidized LDL. A breakdown of apolipoprotein-B (apoB), hydrolysis of the phospholipids, an increase of thiobarbituric acid reactive substances and the generation of aldehydes also occur. Changes in the ratio of lipid to protein, the electrophoretic mobility and the fluorescent properties have also been reported to accompany oxidation of this lipoprotein. The functional changes of oxidized LDL include its recognition by the scavenger receptor on macrophages, its cytotoxicity especially to proliferating cells, its chemotactic properties with respect to monocyte-macrophages and its regulation of platelet-derived growth factor-like protein (PDGFc) production by endothelial cells. In this article we summarize some of the contributions to this topic and present speculations relating oxidized LDL to pathological conditions such as atherosclerosis.
Free Radicals↗
Naturally occurring carbonyl compounds are mutagens in Salmonella tester strain TA104.
Strains of Salmonella typhimurium that carry a nonsense mutation at the site of reversion detect a variety of naturally occurring and synthetic carbonyl compounds as direct-acting mutagens. TA104 is reverted efficiently by formaldehyde, alpha, beta-unsaturated aldehydes (enals), and dicarbonyl compounds, such as diacetyl and glutaraldehyde. This strain is much more sensitive to carbonyl mutagenesis than is TA100, a strain previously reported to detect aldehydes as mutagens, or any other characterized strains of Salmonella. Long-chain enals are very toxic to TA104, but addition of a reduced glutathione chase following an incubation period decreases this toxicity, thus enabling the detection of 4-hydroxy-pentenal, a homolog of the lipid peroxidation product, 4-hydroxy-nonenal, as a mutagen. This is the first report of the mutagenicity of a hydroxy-enal, a class of enals produced by lipid peroxidation. Testing conducted with strains that carry the nonsense mutation in different repair backgrounds indicates that the presence of pKM101 and the deletion of the uvrB gene facilitate the detection of enals and dicarbonyls, but not malondialdehyde, as mutagens. Since carbonyl compounds are widely distributed in foods, are generated during cellular metabolism, and are present in body fluids, they may make a significant contribution to the risk of human cancer.
Aldehydes↗
Cytotoxicity, DNA fragmentation and sister-chromatid exchange in Chinese hamster ovary cells exposed to the lipid peroxidation product 4-hydroxynonenal and homologous aldehydes.
The cytotoxic and genotoxic activities of 4-hydroxypentenal (HPE), 4-hydroxyhexenal (HHE), 4-hydroxyoctenal (HOE), 4-hydroxynonenal (HNE) and 4-hydroxyundecenal (HUE) were investigated in Chinese hamster ovary (CHO) cells. All five 4-hydroxyalkenals reduced plating efficiency in a concentration (ranging from 7 to 170 microM) lower than that producing a parallel reduction of trypan blue-excluding cells, but with both methods the increase in molarity needed to obtain a lethal effect was constantly rather small. With all five 4-hydroxyalkenals a significant amount of DNA fragmentation, as revealed either by the alkaline elution assay or by alkaline denaturation followed by chromatographic partition of single- and double-stranded DNA, was detected only after cell exposure to a cytotoxic concentration. HPE, HHE and HOE induced a clear-cut increase of sister-chromatid exchange (SCE) frequency, while that displayed by cells treated with HNE and HUE was minimal, even if dose-dependent and statistically significant. Since 4-hydroxyalkenals have been shown to originate from biomembrane lipids peroxidation, these findings should be taken into consideration in the assessment of the genotoxic role of lipoperoxidation in humans.
Aldehydes↗
Biochemical, structural, and functional properties of oxidized low-density lipoprotein.
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Animals↗
Simulation of lipid peroxidation in low-density lipoprotein by a basic "skeleton" of reactions.
A minimal kinetic model describing lipid peroxidation in low-density lipoprotein (LDL) has been set up. Models have been calculated by numeric integration of the differential equations describing this system consisting of seven reactions and eleven reactants in a single compartment. The model describes the usually observed behavior of the reaction system, showing that the crucial intermediate is the lipid peroxyl radical (LOO.). During different stages of the reaction, depending on the presence of antioxidants (alpha-tocopherol), different pathways in the reaction scheme become active. Simulation also demonstrates that tocopherol-mediated propagation can occur under certain conditions, i.e., a low rate of initiation. This, however, does not mean that tocopherol enhances lipid peroxidation in LDL, as without tocopherol the process would be much faster. Further extension of the basic model by inclusion of a hypothetical antioxidant leads to a model which is capable of describing Cu(2+)-induced LPO over the whole lag phase up to full propagation.
Antioxidants↗
Modification of low density lipoprotein with 4-hydroxynonenal induces uptake by macrophages.
There is indirect evidence that the oxidation of low density lipoprotein (LDL) may be involved in the development of atherosclerosis. Modification of LDL by oxidation may lead to its unregulated uptake by intimal macrophages to form foam cells. Because of the complexity of events occurring during LDL oxidation, we have tested whether LDL modified directly with 4-hydroxynonenal (HNE), a major propagation product formed during lipid peroxidation and known to be present in oxidized LDL, could bring about lipid loading of macrophages. Modification was accomplished by incubating LDL with various concentrations of HNE up to 7.5 mM. When LDL was derivatized with lower concentrations of HNE, concentration-dependent increases were observed in the covalent binding of HNE to apolipoprotein B (apo B), the blockage of the epsilon-amino groups on lysine residues of apo B, and the relative electrophoretic mobility of LDL. Decreases were observed in degradation of the modified LDL by the J774 cell line, mouse peritoneal macrophages, and smooth muscle cells. Modification of LDL by incubation with the higher concentrations of HNE resulted in LDL aggregation. This modification was associated with marked increases in the macrophage degradation of LDL. Degradation of aggregated HNE-modified LDL increased linearly with incubation time, leading to lipid loading of these cells as observed by oil red O staining and cholesterol accumulation. Uptake appeared to occur by phagocytosis, since cytochalasin D, an inhibitor of phagocytosis, quantitatively inhibited uptake and degradation of labeled HNE LDL. Uptake did not appear to be mediated by either the LDL receptor or the scavenger receptor, since competition with excess amounts of LDL or acetyl LDL failed to inhibit degradation of labeled, aggregated HNE LDL. Saturation of degradation of HNE LDL by macrophages could be attributed, in part, to steric hindrance, since both excess HNE LDL and other particulate ligands could inhibit this degradation. These studies suggest that interaction of LDL with HNE formed during lipid peroxidation could be responsible for structural modifications leading to unregulated uptake of the lipoprotein by tissue macrophages. This could partially explain lipid loading or foam cell formation in atherosclerosis.
Aldehydes↗
Reaction of glutathione with conjugated carbonyls.
1. GSH reacts with conjugated carbonyls according to the equation: GSH+R-CH=CH-COR in equilibrium R-CH(SG)-CH2-COR. The forward reaction follows second order, the reverse reaction first order kinetics. It is assumed that this reaction reflects best the ability of conjugated carbonyls to inactivate SH groups in biological systems. 2. The rate of forward reaction increases with pH approx. parallel with alphaSH. Besides OH- ions also proton donors (e.g. buffers) increase the rate. The catalytic effect of pH and buffer is interpreted in view of the reaction mechanism. 3. The equilibrium constants as well as the rate constants for forward (k1) and reverse reaction show an extreme variation depending on the carbonyl structure. Acrolein and methyl vinyl ketone (k1 = 120 and 32 mol-1 sec-1, resp.) react more rapidly than any other carbonyl to give very stable adducts (half-lives for reverse reaction 4.6 and 60.7 days, resp). Somewhat less reactive are 4-hydroxy-2-alkenals and 4-ketopentenoic acid (k1 between 1 and 3 mol-1 sec-1), but they also form very stable adducts showing half-lives between 3.4 and 19 days. All other carbonyl studied react either very slowly (e.g. citral, ethly crotonate, mesityl oxide, acrylic acid) or form very labile adducts (crotonal, pentenal, hexenal, 3-methyl-butenone). Comparing biological activities of conjugated carbonyls their reactivity towards HS (k1) and the stability of the adducts must be considered.
Aldehydes↗
Aerobic oxidation of p-hydroquinone by horse radish peroxidase in the presence of a thiol and MnCl2.
In the presence of MnCl2 and a thiol (glutathione, cysteine, 2-nitro-5-thiobenzoic acid) horse radish peroxidase oxidizes p-hydroquinone to p-benzoquinone which in turn immediately adds the thiol present yielding 2-S-substituted p-hydroquinone.
Horseradish Peroxidase↗