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PubMed1987

Alkaline phosphatase inactivation by mixed function oxidation systems.

Alkaline phosphatase is inactivated by mixed function oxidation systems. OH. radicals, generated via an ascorbate-modified Haber-Weiss cycle or a Fenton-type reaction, seem to be responsible for the protein oxidative damage. Experiments with hydroxyl radical scavengers, enzyme substrates, products, and metal cofactors suggest that a "site-specific" radical attack takes place at or near the active center. Vitamin E fails to protect alkaline phosphatase; uric acid, instead, is particularly effective in shielding the protein against covalent modifications.

Alkaline Phosphatase↗
PubMed1987

4-Hydroxy-2,3-trans-nonenal stimulates microsomal lipid peroxidation by reducing the glutathione-dependent protection.

Glutathione (GSH) protects liver microsomes against lipid peroxidation. This is probably due to the reduction of vitamin E radicals by GSH, a reaction catalyzed by a membrane-bound protein. Pretreatment of liver microsomes with 0.1 or 1mM 4-hydroxy-2,3-trans-nonenal (HNE), a major product of lipid peroxidation, reduces the GSH-dependent protection. GSH and vitamin E concentrations are not affected by this pretreatment. Pretreatment with 0.1 mM N-ethyl maleimide (NEM), a synthetic sulfhydryl reagent, resulted in a reduction similar to that with HNE of the GSH-dependent protection against lipid peroxidation. The reduction of the GSH-dependent protection by HNE and NEM is probably the result of inactivation of the membrane-bound protein by covalent binding to an essential SH group on the protein. If the GSH-dependent protection would proceed via the microsomal GSH transferase, pretreatment with NEM, which activates the microsomal GSH transferase, should enhance the GSH-dependent protection. Actually a decrease in the GSH-dependent protection is found. Apparently the GSH-dependent protection does not proceed via the microsomal GSH transferase. Also the microsomal phospholipase A2 is not involved, since addition of 0.1 mM mepacrine, an inhibitor of phospholipase A2, did not preclude the GSH-dependent protection. Once the process of lipid peroxidation, either in vivo or in vitro, has started, the protection of liver microsomes by GSH is less effective. This might be the result of formed HNE. In this way an endproduct of lipid peroxidation stimulates the process that generates this product.

Aldehydes↗
PubMed1989

Studies of ascorbate-dependent, iron-catalyzed lipid peroxidation.

We have previously observed that both Fe(II) and Fe(III) are required for lipid peroxidation to occur, with maximal rates of lipid peroxidation observed when the ratio of Fe(II) to Fe(III) is approximately one (J. R. Bucher et al. (1983) Biochem. Biophys. Res. Commun. 111, 777-784; G. Minotti and S. D. Aust (1987) J. Biol. Chem. 262, 1098-1104). Consistent with the requirement for both Fe(II) and Fe(III), ascorbate, by reducing Fe(III) to Fe(II), stimulated iron-catalyzed lipid peroxidation but when the ascorbate concentration was sufficient to reduce all of the Fe(III) to Fe(II), ascorbate inhibited lipid peroxidation. The rates of lipid peroxidation were unaffected by the addition of catalase, superoxide dismutase, or hydroxyl radical scavengers. Exogenously added H2O2 also either stimulated or inhibited ascorbate-dependent, iron-catalyzed lipid peroxidation apparently by altering the ratio of Fe(II) to Fe(III). Thus, it appears that the prooxidant effect of ascorbate is related to the ability of ascorbate to promote the formation of a proposed Fe(II):Fe(III) complex and not due to oxygen radical production. The antioxidant effect of ascorbate on iron-catalyzed lipid peroxidation may be due to complete reduction of iron.

Animals↗
PubMed1996

Iron transport into erythroid cells by the Na+/Mg2+ antiport.

Rabbit erythroid cells can take up non-transferrin-bound iron by a high-affinity and a low-affinity transport mechanism (Hodgson et al. (1995) J. Cell. Physiol. 162, 181-190). The latter process, which is present in mature erythrocytes as well as reticulocytes, was investigated in this study using rabbit reticulocytes and erythrocytes. Iron uptake was optimal in isotonic KCI (pH 7.0), was shown to be much greater for Fe(II) than Fe(III), to be saturable with a Km value of approx. 15 microM Fe(II), temperature-dependent and inhibited by inhibitors of cell energy metabolism, by Na+ and many divalent cations and by several known inhibitors of membrane cation transport mechanisms. Uptake was more rapid with rabbit than with rat or human erythrocytes. The Fe(II) transport process was much more sensitive to inhibition by Mg2+ than by Ca2+ and the inhibition by both Mg2+ and Na+ was of competitive type. Cells depleted of intracellular Mg2+ by the use of the ionophore A23187 had low rates of Fe(II) uptake. High rates of uptake could be achieved by replenishment of intracellular Mg2+, and the Mg(2+)-dependent uptake of Fe(II) was inhibited by the same reagents which reduced the uptake by untreated cells. Many features of the Fe(II) transport process are very similar to those of the previously described Na+/Mg2+ antiport. These features, plus the stimulation of Fe(II) uptake by intracellular Mg2+ and inhibition by extracellular Mg2+ or Na+, strongly suggest that the iron is transported into the cells by the antiport.

Adenosine Triphosphate↗
PubMed1988

Studies on lipid peroxidation in rat liver nuclei and isolated nuclear membranes.

Non-enzymatic and enzymatically-driven lipid peroxidation processes were studied in rat liver nuclei and isolated nuclear membranes, by evaluating the formation of thiobarbituric acid-chromophore, free malondialdehyde, lipofuscin-like pigments, and the degradation of polyunsaturated fatty acids of the nuclear membrane lipids. The results obtained show that: (1) both non-enzymatic and enzymatically driven lipid peroxidation processes are operative in cell nuclei and isolated nuclear membranes; (2) only for isolated nuclear membranes, a good qualitative and up to a great extent quantitative correlation between malondialdehyde and lipofuscin-like pigment formation was obtained; (3) there is a qualitative but not quantitative correlation between malondialdehyde formation and polyunsaturated fatty acid degradation; (4) lipid peroxidation processes in isolated nuclear membranes and intact nuclei have an essentially identical kinetic behaviour. No statistical differences in the relative increases in the concentrations of malondialdehyde and lipofuscin-like pigments or in the degradation of polyunsaturated fatty acids were obtained, when the two systems were compared, except in the presence of NADPH-ADP-Fe3+, which induced a significantly larger degradation of polyunsaturated fatty acids in isolated nuclear membranes than in intact nuclei, and (5) no malondialdehyde-DNA fluorescent adduct formation was observed in any of the experimental groups studied, as inferred from the characteristics of the fluorescent spectra of lipofuscin-like pigments extracted from incubated nuclear preparations.

Adenosine Diphosphate↗
PubMed1975

Complexes between synthetic polymer ligands and ferri-delta and ferro-protoporphyrin IX.

The complexes of synthetic polymer ligands, i.e. poly-L-lysine, poly-4-vinyl-pyridine, poly-N-vinyl-2-methylimidazole and the higher branched polyethyleneimine, with ferri- or ferro-protoporphyrin IX were studied from the standpoint of polymer ligand effects by comparison with those of their monomeric model ligand complexes and poly-gamma-benzyl-L-glutamate containing an imidazole nucleus at the chain end. The coordination numbers and formation constants were determined optically and their structures were also estimated. The coordination number of a poly-L-lysine complex was two, but those of other polymer ligand complexes were one. One of the polymer effects, which was indicated by the large formation constants of the polymer complexes, was caused by the increment of the local ligand concentration around the polymer chain. Another was caused by the conformational effect of an alpha-helical structure in the poly-L-lysine complexes. The interaction of a poly-L-lysine-heme complex with molecular oxygen was also studied. An observed pseudo-allosteric phenomenon may be due to the specific structure of a poly-L-lysine complex which is different from those of other polymer ligand complexes.

Allosteric Site↗
PubMed1989

An investigation on lipoperoxidation mechanisms in boar spermatozoa.

Aerobic incubation of washed boar spermatozoa in a heavy metal free medium at 37 degrees C results in a peroxidative breakdown of membrane phospholipids as revealed by malondialdehyde production. In the presence of iron ions, alone and with ascorbate, the amount of malondialdehyde produced increases noticeably. Alkoxy and lipoperoxy radicals are likely involved in these peroxidative processes, while OH. radical does not seem to be essential in the pathway of malondialdehyde formation.

Animals↗
PubMed1993

Inhibition of in vitro lipid peroxidation by 21-aminosteroids. Evidence for differential mechanisms.

In a previous report (Ryan and Petry, Arch Biochem Biophys 300: 699-704, 1993), the effects of two 21-aminosteroids (U-74500A and U-74006F) on the oxidation and reduction of iron in a buffer/organic solvent system were investigated. In those studies, U-74500A was found to be an efficient iron reductant and potential iron chelator, whereas U-74006F had little effect on iron redox chemistry. As an extension of those studies, we now report the effects of U-74006F and U-74500A on lipid peroxidation in systems that are dependent upon iron oxidation/reduction. In liposomes, U-74500A inhibited ADP:Fe(II)-dependent lipid peroxidation in a concentration-dependent manner, whereas U-74006F was minimally effective in this system. The mechanism of U-74500A-dependent inhibition probably involved interactions with iron, as iron oxidation was inhibited in the presence of this compound. No effects on iron oxidation were observed in the presence of U-74006F. Addition of Ferrozine to liposomal incubation mixtures indicated that at least two iron pools were present in samples containing U-74500A, one immediately bound by Ferrozine, and another that was bound more slowly. Furthermore, ADP:Fe(III)/ascorbate-dependent lipid peroxidation was blocked completely by U-74500A, presumably by formation of a redox inert complex upon reduction of the iron. U-74500A partially protected ADP:Fe(II) from oxidation by H2O2 and lipid hydroperoxides, indicating that the U-74500A:iron complex was stable in the presence of biologically relevant oxidants. U-74006F did not markedly affect iron oxidation or reduction when incorporated into phospholipid liposomes. In microsomal lipid peroxidation systems containing ADP:Fe(III) and NADPH, both U-74500A and U-74006F inhibited lipid peroxidation. U-74006F-dependent inhibition of microsomal lipid peroxidation was dependent on both NADPH and Fe(III). Further, it was enhanced when U-74006F was allowed to preincubate in this system prior to iron addition. Preincubation of U-74006F with microsomes, NADPH, and ADP:Fe(III) produced several metabolites detectable by HPLC. These results suggest that U-74500A inhibits lipid peroxidation by directly affecting iron redox chemistry, whereas U-74006F-mediated inhibition is enhanced by preincubation with a metabolically competent microsomal system.

Animals↗
PubMed1994

Tamoxifen and hydroxytamoxifen as intramembraneous inhibitors of lipid peroxidation. Evidence for peroxyl radical scavenging activity.

Tamoxifen (TAM) is the antiestrogen most widely used in the chemotherapy and chemoprevention of breast cancer. It has been reported that TAM and its more active metabolite 4-hydroxytamoxifen (OHTAM) induce multiple cellular effects, including antioxidant actions. Here sarcoplasmic reticulum membranes (SR) were used as a simple model of oxidation to clarify the antioxidant action type and mechanisms of these anticancer drugs on lipid peroxidation induced by Fe2+/ascorbate and peroxyl radicals generated by the water-soluble 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH) and by the lipid-soluble 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN). Peroxidation was monitored by different assay systems, namely cis-parinaric acid (PnA) fluorescence quenching, production of thiobarbituric acid-reactive substances, polyunsaturated fatty acids (PUFA) degradation and oxygen consumption. TAM and OHTAM are efficient inhibitors of lipid peroxidation induced by Fe2+/ascorbate and strong intramembraneous scavengers of peroxyl radicals generated either in the water or lipid phases by AAPH and AMVN, respectively. However, these drugs are not typical chain-breaking antioxidant compounds as compared with vitamin E. Additionally, their antioxidant effectiveness enhances the protective capacity of vitamin E against lipid peroxidation induced by AMVN. OHTAM is a more powerful intramembraneous inhibitor of lipid peroxidation as compared with TAM; this effectiveness not correlating with alterations on membrane fluidity may be due to the presence of a hydrogen-donating HO-group in the OHTAM molecule and its preferential location in the outer bilayer regions where it can donate the hydrogen atom to quench free radicals capable of initiating the membrane oxidative degradation. The stronger OHTAM intramembraneous scavenger capacity over TAM also correlates with its higher partition in biomembranes. Therefore, the strong peroxyl radical scavenger activity of OHTAM in the hydrophobic membrane phase may putatively contribute to the mechanisms of cytostatic and chemopreventive action of its promoter TAM on development of breast cancer.

Amidines↗
PubMed1994

3,5,5-Trimethylhexanoylferrocene induction of heme oxygenase activity in normal hepatocytes.

Recent work showed that the combination of 50 microM glutethimide plus 50 microM ferric nitrilotriacetate (FeNTA) synergistically induces heme oxygenase (HO) activity in cultured chick embryo liver cells (Cable et al., Biochem Biophys Res Commun 168: 176-181, 1990). This synergistic induction is due to increased heme synthesis, which then acts to increase HO gene transcription. The aim of the current studies was to characterize the effects on hepatic heme metabolism of (3,5,5-trimethylhexanoyl)ferrocene (TMH-ferrocene), which causes hepatic iron-loading in rats. Unlike FeNTA, TMH-ferrocene alone maximally induced HO activity at 5-10 microM TMH-ferrocene. At higher concentrations, HO activities declined, as did total cellular protein synthesis. Induction of HO was maximal after a 12-hr exposure to TMH-ferrocene, similar to induction by glutethimide plus FeNTA. The effect of TMH-ferrocene on HO could not be ascribed to greater cellular uptake of iron, since cell-associated iron levels were higher after FeNTA than after TMH-ferrocene treatment. TMH-ferrocene (up to 20 microM) did not induce delta-aminolevulinic acid synthase activity. Uroporphyrin accumulation in cells treated with TMH-ferrocene was minimal, but the combination of TMH-ferrocene and glutethimide caused a synergistic increase in uroporphyrin accumulation, similar to treatment with glutethimide plus FeNTA. 4,6-Dioxoheptanoic acid, an inhibitor of heme synthesis, blocked the induction of HO caused by glutethimide and FeNTA, but did not decrease the induction of HO by TMH-ferrocene. TMH-ferrocene-mediated induction of HO does not appear to be due to lipid peroxidation, since malondialdehyde formation was greater for ferrocene (a structural analog of TMH-ferrocene that does not induce HO) than for TMH-ferrocene. Furthermore, the anti-oxidant, butylated hydroxyanisole, which prevented lipid peroxidation, decreased HO induced by glutethimide plus FeNTA, but butylated hydroxyanisole did not affect HO induced by TMH-ferrocene. We conclude that, unlike the combination of glutethimide plus FeNTA, TMH-ferrocene induces HO activity by a mechanism that is independent of cellular heme synthesis.

Animals↗
PubMed1995

Metallothionein protects DNA from copper-induced but not iron-induced cleavage in vitro.

Iron and copper ions mediate generation of reactive oxygen radicals from O2 and H2O2 by the Fenton reaction: these radicals are capable of damaging DNA. We studied (a) the ability of these metals to induce double-strand breaks in DNA in vitro in the presence of H2O2 and ascorbic acid as donors of reactive oxygen, and (b) the ability of the metal-binding protein metallothionein (MT) to protect DNA from damage. Strand cleavage was measured by loss of fluorescence after binding to ethidium bromide and by increased mobility of DNA in agarose. The results show that Cu(II), Fe(II) and Fe(III) all can induce damage to calf thymus DNA under our experimental conditions. Cu(II)-induced DNA damage was dose-dependent and the degree of damage was proportional to the concentration of H2O2. On the other hand, DNA fragmentation was significant only in the presence of high concentrations of Fe(II) or Fe(III). Addition of Zn-MT to the reaction mixture prior to addition of Cu(II) inhibited fragmentation of DNA in a dose-dependent manner but had little effect on iron induced damage. Other proteins (histone or albumin) were not effective in protecting DNA from Cu-induced damage, as compared to Zn-MT. The formation of Cu(I) from Cu(II) in the presence of hydrogen peroxide and ascorbate was also inhibited by addition of Zn-MT. Thus, MT may protect DNA from damage by free radicals by sequestering copper and preventing its participation in redox reactions.

Animals↗