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S D Aust

Publications and source records attributed to S D Aust.

230 records · Page 13Linked to original sources
PubMedDate not supplied

The role of iron in the initiation of lipid peroxidation.

Iron is required for the initiation of lipid peroxidation. Evidence is presented that lipid peroxidation requires both Fe3+ and Fe2+, perhaps with oxygen to form a Fe3+-dioxygen-Fe2+ complex. Other mechanisms of initiation, mostly involving the iron-catalyzed formation of hydroxyl radical, are described and discussed from both theoretical and experimental view points.

Free Radicals↗
PubMedDate not supplied

Toxicity and microsomal enzyme induction effects of several polybrominated biphenyls of Firemaster.

Some toxicological and pharmacological effects of 2,4,5,2',5'-penta- (congener 1), 2,3,4,2',4',5'-hexa- (congener 5), 2,4,5,3',4',5'-hexa- (congener 6), 2,3,4,5,3',4',-hexa- (congener 7), and 2,3,4,5,2',3',4'-heptabromobiphenyl (congener 9) were evaluated in male rats given a single 90 mg/kg ip injection and killed seven days later. Only congener 7 depressed body weight gain, spleen and thymus weights, and caused severe histopathological changes in the thymus. Congener 7 caused the largest increase in liver weight and the most changes in liver pathology while congener 1 failed to enlarge this organ and caused the mildest ultrastructural changes. Liver microsomes were isolated and evaluated for enzyme induction from all treated rats except those administered congener 6, which was previously identified as a mixed-type enzyme inducer (Dannan et al., 1978b). All congeners increased the liver microsomal cytochrome P-450 content, but only congener 7 shifted the carbon monoxide difference spectrum absorption maximum to 448.0 nm. The microsomal ethyl isocyanide difference spectrum 455/430 nm ratio was increased the most by congener 7 (3 fold). All congeners increased cytochrome P-450 reductase and microsomal epoxide hydrase activities by nearly 1.5-3 fold. Congener 7 failed to induce aminopyrine-N-demethylase activity but the remaining congeners increased it by 2 fold. Congener 7 was the most effective inducer of benzo[a]pyrene hydroxylase and p-nitrophenol UDP-glucuronyl transferase. These results add to the suggestion that the presence of an ortho halogen on a polyhalogenated biphenyl does not completely abolish toxicity or 3-methylcholanthrene-type microsomal enzyme induction.

Animals↗
PubMedDate not supplied

Redox cycling and lipid peroxidation: the central role of iron chelates.

Toxicities associated with redox cycling, including lipid peroxidation, are often attributed to the hydroxyl radical through a superoxide-driven, iron-catalyzed Haber-Weiss reaction. However, other cellular reducing agents more prevalent than superoxide, i.e., glutathione, ascorbate, cysteine and certain enzymes, can also reduce chelated iron and thereby initiate lipid peroxidation which is not inhibited by superoxide dismutase. The autoxidation of ferrous chelates yields partially reduced oxygen intermediates similar to those produced during the iron-catalyzed Haber-Weiss reaction. The mechanism of their formation, and the nature of the strong oxidant responsible for the initiation of lipid peroxidation are poorly understood, but are apparently influenced by the chelation of the iron. These conclusions stem from experiments which demonstrated variable amounts of inhibition of lipid peroxidation, dependent on the autoxidation of various ferrous chelates, by added superoxide dismutase or catalase. In addition, certain ferrous chelates are unable to initiate peroxidation of lipids in a liposomal configuration, yet capable of initiating peroxidation of lipids which were dispersed with a detergent. The results of these studies point out the need to isolate and identify the predominant physiological iron chelates for assessment of their ability to participate in redox related toxicities within the cell.

Adenosine Diphosphate↗
PubMedDate not supplied

Engineering a disulfide bond in recombinant manganese peroxidase results in increased thermostability.

Manganese peroxidase (MnP) produced by Phanerochaete chrysosporium, which catalyzes the oxidation of Mn(2+) to Mn(3+) by hydrogen peroxide, was shown to be susceptible to thermal inactivation due to the loss of calcium [Sutherland, G. R. J.; Aust, S. D. Arch. Biochem. Biophys. 1996, 332, 128-134]. The recombinant enzyme, lacking glycosylation, was found to be more susceptible [Nie, G.; Reading, N. S.; Aust, S. D. Arch. Biochem. Biophys. 1999, 365, 328-334]. On the basis of the properties and structure of peanut peroxidase, we have engineered a disulfide bond near the distal calcium binding site of MnP by means of the double mutation A48C and A63C. The mutant enzyme had activity and spectral properties similar to those of native, glycosylated MnP. The thermostabilities of native, recombinant, and mutant MnP were studied as a function of temperature and pH. MnPA48C/A63C exhibited kinetics of inactivation similar to that of native MnP. The addition of calcium decreased the rate of thermal inactivation of the enzymes, while EGTA increased the rate of inactivation. Thermally treated MnPA48C/A63C mutant was shown to contain one calcium, and it retained a percentage of its original manganese oxidase activity; native and recombinant MnP were inactivated by the removal of calcium from the protein.

Base Sequence↗
PubMedDate not supplied

Effects of (+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane (ADR-529) on iron-catalyzed lipid peroxidation.

ADR-529 [(+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane], a nonpolar, cyclic analogue of EDTA, protects against anthracycline cardiotoxicity in vivo. The protective mechanism presumably involves chelation of iron by a hydrolysis product of ADR-529, thus preventing the formation of reactive iron/oxygen species which can damage membrane lipids. We investigated the effects of ADR-529 and its hydrolysis products (the tetraacid and the diacid diamide) on NADPH- and ADP-Fe(3+)-dependent lipid peroxidation of rat liver microsomes and liposomes in the presence of cytochrome P-450 reductase. Hydrolyzed ADR-529 products caused inhibition of lipid peroxidation when in excess of the iron concentration. However, no inhibition of lipid peroxidation was detected by similar concentrations of nonhydrolyzed ADR-529. Microsomes did not affect the inhibition of lipid peroxidation, suggesting that rat liver microsomes do not hydrolyze ADR-529. Similarly, the diacid diamide hydrolysis product of ADR-529 inhibited ferritin- and adriamycin-iron-dependent liposomal lipid peroxidation in a concentration-dependent manner. No correlation between partially reduced oxygen species (O2.- and .OH; as measured by electron spin resonance) and lipid peroxidation (as assayed by malondialdehyde formation) was observed, suggesting that liposomal lipid peroxidation was strictly an iron-dependent phenomenon. These results suggest that inhibition of lipid peroxidation by iron chelation may be related to the protective effects of ADR-529 on in vivo anthracycline toxicity.

Animals↗
PubMedDate not supplied

Pathologic effects of 2,2',4,4',5,5'-and 2,3',4,4',5,5'-hexabromobiphenyl in white leghorn cockerels.

Pathologic effects of 2,2',4,4',5,5'-hexabromobiphenyl (HBB), 2,3',4,4',5,5'-HBB, and a commercial mixture of polybrominated biphenyls (PBB) were compared in White leghorn cockerels. Diets containing 1, 10, or 100 ppm PBB, 4 or 10 ppm 2,3',4'4',5,5'-HBB, or 10 or 62 ppm 2,2',4,4',5,5'-HBB were fed for 28 days. Doses of 10 ppm of each chemical were used to provide a direct comparison of toxicity. Since nearly 4% of PBB consists of 2,3',4,4',5,5'-HBB and approximately 62% consists of 2,2',4,4',5,5'-HBB, effects of doses of 4 and 62 ppm, respectively, were compared with effects of 100 ppm of PBB to determine if either of the congeners were mainly responsible for the pathologic effects caused by the mixture. Liver weights were increased in cockerels fed diets containing 62 ppm of 2,2',4,4',5,5'-HBB or 10 or 100 ppm PBB. Hepatocytes were enlarged and vacuolated and lymphoid cells of the bursa of Fabricius were depleted by 10 ppm 2,3',4,4',5,5'-HBB, ppm 2,2',4,4',5,5'-HBB, and 10 or 100 ppm PBB. These dietary concentrations caused ultrastructural changes in hepatocytes consisting of vacuolation, increased smooth endoplasmic reticulum, swollen mitochondria, and disruption of mitochondrial cristae. When either of the congeners were given in concentrations relative to their concentrations in PBB, they were less toxic than the mixture. When concentrations in diets were equal, PBB caused more severe effects than 2,3',4,4',5,5'-HBB. The least effects were seen with 2,2',4,4',5,5'-HBB. Results indicate that the two congeners chosen for study are not individually as toxic as the parent mixture.

Animals↗