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Biomedical subjects

S D Aust

Publications and source records attributed to S D Aust.

At least 199 records · Page 11Linked to original sources
PubMed1982

Purification of polybrominated biphenyl congeners.

A commercial preparation of polybrominated biphenyls (Firemaster BP-6) was fractionated by preferential acetone solubilization and a number of PBB congeners were purified from the resulting fractions by repeated recrystallization, alumina adsorption column chromatography, and reversed-phase Lipidex-500 column chromatography. The applicability of reversed-phase Lipidex-5000 chromatography for the separation of highly structurally similar brominated biphenyl congeners that otherwise could not be separated by alumina chromatography or recrystallization was demonstrated. In total, seven congeners were purified, including one whose structure was assigned as 2,3,4,5,3',4'-hexabromobiphenyl.

Biphenyl Compounds↗
PubMed1982

Polybrominated biphenyls as promoters in experimental hepatocarcinogenesis in rats.

Female Sprague Dawley rats were fed polybrominated biphenyls (PBB) for six months after a 70% partial hepatectomy and diethylnitrosamine administration (10 mg/kg body weight) to determine if PBB could serve as a tumor promoter in a two stage hepatocarcinogenesis test system. Firemaster BP-6, a commercial mixture of PBB, and its major congener, 2,2',4,4',5,5'-hexabromobiphenyl (HBB) were used in this study. Tumor promoting ability was assessed by measuring enzyme altered foci exhibiting gamma glutamyl transpeptidase activity. Dietary concentrations of 10 and 100 p.p.m. of the mixture of PBB and of HBB were found to be promoters of hepatocarcinogenesis. The mixture of PBB had a greater tumor promoting ability than HBB.

Acyltransferases↗
PubMed1982

Inhibition of metabolic cooperation in Chinese hamster V79 cells in culture by various polybrominated biphenyl (PBB) congeners.

Using an in vitro assay system to measure a form of cell-cell communication in Chinese hamster V79 cells, several purified polybrominated biphenyl (PBB) congeners were analyzed for their ability to affect colony-forming ability and "metabolic cooperation" in these cells. Results clearly demonstrate the assay's ability to distinguish differences in the cytotoxic and metabolic cooperation-inhibiting properties of these congeners related to their structure. It appears that if a carbon ortho to the bridge carbon of each phenyl ring is brominated, the molecule has the property by which metabolic cooperation is inhibited. The results suggest that several PBB congeners share at least one property associated with several known tumor promoters, such as the phorbol esters. Although we have not ruled out that the mixture of PBB congeners might contain initiators or that various PBB metabolites would be mutagen/initiators, based on these and other results, it was concluded that the reported carcinogenic potential of PBB seems to be mediated by its action as a tumor promoter, rather than as a complete carcinogen or an initiator.

Animals↗
PubMed1981

Superoxide dependent lipid peroxidation.

Rat liver microsomal NADPH-dependent lipid peroxidation and xanthine oxidase-promoted lipid peroxidation were reviewed and compared to see if a unified mechanism is involved in each system. These systems were also compared to hydroxyl radical-dependent lipid peroxidation in order to determine the physiological significance of the different mechanisms of lipid peroxidation. Fenton's reagent very readily promotes lipid peroxidation, which is inhibited by catalase and hydroxyl radical traps but not by superoxide dismutase. However, the addition of ADP to Fenton's reagent results in a type of lipid peroxidation that is not inhibited by hydroxyl radical traps and the amount of hydroxyl radical spin trap adducts formed is much less. Xanthine oxidase-promoted lipid peroxidation is not inhibited by catalase and is greatly stimulated by ADP. Microsomal NADPH-dependent lipid peroxidation is also dramatically stimulated by ADP in Tris buffer but not in phosphate buffer. Hydroxyl radical traps are without effect in both microsomes and xanthine oxidase-promoted lipid peroxidation. These results suggest several in vitro mechanisms for the initiation of lipid peroxidation but do not support the hydroxyl radical for a role in physiological lipid peroxidation.

Animals↗
PubMed1979

The mechanism of NADPH-dependent lipid peroxidation. The propagation of lipid peroxidation.

NADPH-dependent lipid peroxidation occurs in two distinct sequential radical steps. The first step, initiation, is the ADP-perferryl ion-catalyzed formation of low levels of lipid hydroperoxides. The second step, propagation, is the iron-catalyzed breakdown of lipid hydroperoxides formed during initiation generating reactive intermediates and products characteristic of lipid peroxidation. Propagation results in the rapid formation of thiobarbituric acid-reactive material and lipid hydroperoxides. Propagation can be catalyzed by ethylenediamine tetraacetate-chelated ferrous ion, diethylenetriamine pentaacetic acid-chelated ferrous ion, or by ferric cytochrome P-450. However, cytochrome P-450 is destroyed during propagation.

Animals↗
PubMed1978

Induction of drug metabolizing enzymes in polybrominated biphenyl-fed lactating rats and their pups.

Polybrominated biphenyls (PBBs) cause a mixed-type (phenobarbital- plus 3-methylcholanthrene-like) induction of liver microsomal drug metabolizing enzymes in rats. However, 2,2',4,4',5,5'-hexabromobiphenyl and 2,2',3,4,4',5,5'-heptabromobiphenyl, which together comprise less than 80% of PBBs (FireMaster), were shown to be strictly phenobarbital-type inducers. Other components (unidentified) must therefore cause the 3-methylcholanthrene-like effects. The potential for PBBs to exert effects on neonates through milk was examined. Lactating rats were fed 0, 0.1, 1.0, or 10 ppm FireMaster for the 18 days following delivery, at which time mothers and most pups were sacrificed. Pups nursing from mothers fed 10 ppm PBBs showed significant increases in liver weights and microsomal protein, and both mothers and pups had increased cytochrome P-450, aminopyrine demethylation, benzo[a]pyrene hydroxylation, and UDP-glucuronyltransferase. Pups nursing from rats fed 1.0 ppm had increases in microsomal protein, cytochrome P-450, aminopyrine demethylation, and benzo[a]pyrene hydroxylation, while their mothers were unaffected. Several pups from the 0, 0.1, and 1.0 ppm groups were maintained on their mother's diets, raised, and allowed to mate. Their pups showed much the same responses to PBBs as did the original group of pups. The effects on both generations of adult female rats were also comparable. PBBs cause a mixed-type induction in both lactating rats and their nursing pups; PBB components responsible for both aspects of this induction must be transmitted through milk. Nursing rats are approximately tenfold more sensitive to the effects of PBBs in their mother's diets than are the dams. The approximate no-effect level for microsomal induction in nursing rats is 0.1 ppm PBBs in the diet of the adult.

Animal Feed↗
PubMed1978

Studies on the microsomal metabolism and binding of polybrominated biphenyls (PBBs).

The metabolism of polybrominated biphenyls (PBBs) was studied in vitro by using rat liver microsomes in the presence of NADPH and atmospheric O2. Quantitative recoveries of all PBBs were obtained after incubations with control or 3-methylcholanthrene (MC) induced microsomes. Of the twelve major components, losses of only peaks 1 (2,4,5,2',5'-pentabromobiphenyl) and 3 (a hexabromobiphenyl) were observed following incubations with microsomes from phenobarbital (PB)- or PBBS- pretreated rats. Of seven structurally identified PBB components, only peak 1 has a bromine-free para position. Peaks 1, 2, and 5 all have two adjacent unsubstituted carbons, yet only peak 1 is metabolized. Of two dibromobiphenyl model compounds studied, the 2,2'-congener was very rapidly metabolized by PB-induced microsomes whereas its 4,4'-isomer was not. These results suggest that the presence of a free para position is required for the metabolism of brominated biphenyls. Of lesser importance appears to be the number of bromines or the availability of two adjacent unsubstituted carbons. In vivo evidence for the metabolism of peaks 1 and 3 was also provided by their drastically diminished levels in liver and milk extracts. When a 14C-PBB mixture consisting almost exclusively of peaks 4 (2,4,5,2',4',5'-hexabromobiphenyl) and 8 (2,3,4,5,2',4',5'-heptabromobiphenyl) was incubated with PB- or PBBs- induced microsomes and NADPH, only traces of radioactivity remained with the microsomes after extensive extraction. However, less radioactivity was bound to microsomes from MC pretreated or especially control rats. No radioactivity was bound to exogenous DNA included in similar microsomal incubations, regardless of the type of microsomes used. Under the same conditions, [3H]-benzo[a]pyrene metabolites were bound to DNA, and PBB-induced microsomes enhanced this binding more than six-fold.

Animals↗
PubMed1976

Lactoperoxidase-catalyzed lipid peroxidation of microsomal and artificial membranes.

Lactoperoxidase, in the presence of H2O2, I-, and rat liver microsomes, will peroxidize membrane lipids, as evidenced by malondialdehyde formation. Fe3+ assists in the formation of malondialdehyde. Fe3+ can be added at the end of the reaction period as well as at the beginning with equal effectiveness, suggesting that it only acts to assist in the conversion of lipid peroxides, previously formed by lactoperoxidase, to malondialdehyde. The addition of EDTA to the microsomal reaction mixture results in a 40% decrease in malondialdehyde formation. The antioxidant butylated hydroxytoluene will completely block the formation of malondialdehyde. Malondialdehyde formation is not dependent upon the production of superoxide, singlet oxygen, or hydroxyl radicals. Peroxidation of membrane lipids by this system is equally effective in both intact microsomes and in liposomes, indicating that iodination of microsomal protein is not required for lipid peroxidation to occur.

Animals↗
PubMed1976

Paraquat toxicity: proposed mechanism of action involving lipid peroxidation.

The purpose of this study was to investigate the hypothesis that paraquat pulmonary toxicity results from cyclic reduction-oxidation of paraquat with sequential generation of superoxide radicals and singlet oxygen and initiation of lipid peroxidation. In vitro mouse lung microsomes catalyzed an NADPH-dependent, single-electron reduction of paraquat. Incubation of paraquat with NADPH, NADPH-cytochrome c reductase, and purified microsomal lipid increased malondialdehyde production is a concentration dependent manner. Addition of either superoxide dismutase or a single oxygen trapping agent 1,3-dipheylisobenzo furan inhibited paraquat stimulated lipid peroxidation. In vivo, pretreatment of mice with phenobarbital decreased paraquat toxicity, possibly by competing for electrons which might otherwise reduce paraquat. In contrast, paraquat toxicity in mice was increased by exposure to 100% oxygen and by deficiencies of the antioxidants selenium, vitamin E, or reduced glutahione (GSH). Paraquat, given IP to mice, at 30 mg/kg, decreased concentrations of the water-soluble antioxidant GSH in liver and lipid soluble antioxidants in lung. Oxygen-tolerant rats, which hae increased activities of pulmonary enzymes which combat lipid peroxidation, were also tolerant to lethal doses of paraquat as indicated by an increased paraquat LT50. Furthermore, rats chronically exposed to 100 ppm paraquat in the water had elevated pulmonary activities of glucose-6-phosphate dehydrogenase and GSH reductase. These results were consistent with the hypothesis that lipid peroxidation is involved in the toxicity of paraquat.

Anaerobiosis↗