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Biomedical subjects

A Freyberger

Publications and source records attributed to A Freyberger.

At least 37 records · Page 2Linked to original sources
PubMed1994

Influence of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, lipoic acid and L-deprenyl on the interplay between cellular redox systems.

For several years there is controversy concerning the toxic potency of reaction products catalyzed by monoamine oxidase in neurodegenerative processes. There is uncertainty whether products of catecholamine oxidation are pathogenetically relevant factors for neuronal cell death in Parkinson's disease. To date products responsible for impairment of biochemical functions essential for cell viability are not yet identified, and the primary site of damage within the cell is unknown. Ammonia, aldehydes and hydrogen peroxide are formed via monoamine oxidase catalyzed oxidations of primary amines. But which of them, if any, is damaging to the cell? We discuss some aspects of the oxidative stress theory of cell degeneration in relation to toxicity of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and to monoamine oxidation. Furthermore, we consider possible functional relationships of mitochondrial electron transfer reactions, toxicity of MPTP and MAO activity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

The thiobarbituric acid assay reflects susceptibility to oxygen induced lipid peroxidation in vitro rather than levels of lipid hydroperoxides in vivo: a methodological approach.

Although the hypothesis of oxidative stress as a pathogenetic factor of neurodegenerative diseases became a matter of interest recently, direct evidence supporting this hypothesis is rare. The most prominent assay being currently used as an index for lipid peroxidation products in vivo is the thiobarbituric acid assay. Thiobarbituric acid reactive substances are mainly formed during the decomposition of lipid hydroperoxides in vitro. It is questionable however, that all species detectable with thiobarbituric acid are derived from in vivo preformed lipid hydroperoxides. These studies were undertaken to investigate the influence of autoxidation reactions on colour production during the acid heating stage of the assay. If driven aerobically, more than 90% of thiobarbituric acid reactive substances are newly generated in vitro during incubation at 95 degrees C for 75 min. This process can be enhanced by addition of ferric iron. Chain breaking antioxidants like butylated hydroxytoluene decrease colour formation in the absence or in the presence of iron. If driven anaerobically under argon, colour formation was only 10% of aerobically heated homogenates or lipid extracts of human brain tissue. These results may indicate that measurement of thiobarbituric acid reactive substances under the aerobic conditions described here reflects to a great extent the susceptibility of brain tissue or lipids to oxygen-induced formation of lipid hydroperoxides in vitro rather than degradation products of in vivo performed lipid hydroperoxides.

Aged↗
PubMed1990

Oxidative stress: a role in the pathogenesis of Parkinson's disease.

The degeneration of nigro-striatal dopaminergic neurons is considered to be a predominant pathogenetic factor of Parkinson's disease (PD). However, the etiology of this degeneration is not known. Hypotheses assume accumulation of endogenous and/or exogenous toxins as trigger of the disease. An increase in the concentration of free radicals has been suggested to be toxic to cells, especially when combined with certain metals like free iron or copper. The role of melanin in the degenerative process is not clear, but autoxidative reactions such as the oxidation of dopamine (DA) to melanin generating radicals and toxic metabolites seem to enhance the vulnerability of neurons in the substantia nigra (SN). Disappearance of melanin in the SN, increase of total iron and ferric iron, extreme decrease of glutathione (GSH) levels, reduced activity of enzymes involved in the detoxification of hydrogen peroxide, hydroxyl and superoxide radicals (peroxidases, catalase, glutathione peroxidase), an increase of monoamine oxidase B (MAO B) activity and the substantial increase of malondialdehyde, a marker of lipid peroxidation, in the SN seem to indicate a role of an oxidative stress syndrome in the SN causing or aggravating PD.

Aged↗
PubMed1989

Covalent binding to proteins of reactive intermediates resulting from prostaglandin H synthase-catalyzed oxidation of stilbene and steroid estrogens.

Prostaglandin H synthase (PSH) is known to metabolically activate a variety of xenobiotics in vitro by means of its peroxidase activity. Recently, stilbene and steroid estrogens have been found to be cooxidized by ram seminal vesical microsomes, a rich source of PHS, to nonextractable metabolites bound to microsomal protein. To investigate further the nature of this protein binding, different radiolabeled estrogens were incubated with purified PHS, holoenzyme in the presence of various amounts of albumin (BSA), and radioactivity bound to protein was determined after gel electrophoretic separation. Diethylstilbestrol (DES), its analog hexestrol, and the steroid estrogens estrone and 2-hydroxy-estrone were cooxidized by PHS in vitro to metabolites that bound covalently to PHS and to BSA. Although a preferential binding of DES to PHS was found in the presence of excess BSA, reactive intermediates derived from DES, or from the other estrogens, were sufficiently stable to react with the competing nucleophile BSA as well. With respect to the metabolic reactions catalyzed by PHS, in addition to one-electron oxidation of phenolic functions, PHS catalyzed the aromatic hydroxylation of synthetic and steroid estrogens as shown by 3H2O release from regiospecifically labeled compounds and confirmed by product identification. Although DES was extensively metabolized by PHS, its aromatic hydroxylation was minor by comparison to estradiol, a difference possibly related to the compounds' redox potentials. Thus, cooxidation of estrogens in vitro resulted in phenoxy radicals, semiquinones and quinones, reactive intermediates capable of protein binding that may contribute to the adverse effects of stilbene and steroid estrogen observed in vivo and in short-term assays.

Animals↗
PubMed1989

Studies on the stoichiometry of estrogen oxidation catalyzed by purified prostaglandin-H-synthase holoenzyme.

Prostaglandin-H-synthase (PHS) is a key enzyme in the biosynthesis of prostaglandins (PGs) from arachidonic acid and can oxidatively metabolize synthetic and steroidal estrogens. To investigate the relationship between estrogen cooxidation and PG synthesis, purified PHS-holoenzyme was incubated with radiolabeled arachidonic acid and various estrogens, namely diethylstilbestrol (DES), estradiol (E2), 2-hydroxyestradiol (2-OHE2), and 2-methoxyestradiol (2-MeOE2). The amount and pattern of PGs synthesized were analyzed by TLC and HPLC, estrogen metabolism was studied by HPLC. All tested compounds increased conversion of arachidonic acid to PG H2-derived prostanoids. A stoichiometric ratio between net estrogen oxidation and net PG H2 formation of approximately 2:1 for monophenolic compounds (2-MeOE2, E2) and of 1:1 for diphenolic estrogens (DES, 2-OHE2) was found, indicating that estrogens are apparently acting as electron donors for the PHS-peroxidase. In contrast, glutathione was not found to provide electrons for the reduction of PGG2 to PGH2, and rather decreased the conversion of arachidonic acid. The results of this in vitro study are discussed with respect to its implications for the in vivo situation.

Catalysis↗