Metabolism of 4-Hydroxynonenal, a Cytotoxic Lipid Peroxidation Product, in Thymocytes as an Effective Secondary Antioxidative Defense Mechanism

Siems, Werner; Pimenov, A M; Esterbauer, Hermann; Grune, Tilman

doi:10.1093/oxfordjournals.jbchem.a021969

Cited by 22 publications

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“…This rate is similar to the uptake of oleate by the perfused rat liver (37). Note that part of the carbon derived from the catabolism of 4-hydroxy- [3,[4][5][6][7][8][9][10][11][12][13] C 2 ]nonanoate is not converted to acetyl-CoA but is released as shorter carboxylic acids into the perfusate (supplemental Table 2). …”

Section: ⅐Gmentioning

confidence: 55%

“…The mass isotopomer distribution of acetyl-CoA labeled from 4-hydroxy- [3,[4][5][6][7][8][9][10][11][12][13] C 2 ]nonanoate allows us to calculate the contributions of pathways A and B to the production of acetyl-CoA from this substrate. Pathways A and B yield three and four acetyl-CoA, respectively, with one acetyl-CoA being labeled in each pathway.…”

Section: -Phosphoacyl-coas In 4-hydroxyacid Metabolismmentioning

confidence: 99%

“…This is the site of fatty acid ␣-oxidation (20), which, in the present case, forms [ 13 C]formate from 4-hydroxynonanoate labeled on C-3. Given the low labeling of acetyl-CoA and its proxies formed from 4-hydroxy [3][4][5][6][7][8][9][10][11][12][13] C]nonanoate (Fig. 8A), it is likely that pathway B is peroxisomal and that pathway A is mitochondrial.…”

Section: -Phosphoacyl-coas In 4-hydroxyacid Metabolismmentioning

confidence: 99%

“…Some unsaturated 4-hydroxyacids are derived from 4-hydroxynonenal and 4-hydroxyhexenal, which are products of lipid peroxidation (1). The metabolism of 4-hydroxynonenal has been extensively studied, especially its conjugation with glutathione (2), covalent modification of proteins (3,4), and conversion to 4-hydroxynonenoate, 4-hydroxynonanoate and 1,4-dihydroxynonene, as well as its role in inflammatory processes (1,(5)(6)(7)(8)(9)(10)(11). However, the catabolism of its carbon skeleton has not been unraveled.…”

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Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

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4-Hydroxyacids are products of ubiquitously occurring lipid peroxidation (C 9 , C 6 ) or drugs of abuse (C 4 , C 5 ). We investigated the catabolism of these compounds using a combination of metabolomics and mass isotopomer analysis. Livers were perfused with various concentrations of unlabeled and labeled saturated 4-hydroxyacids (C 4 to C 11 ) or 4-hydroxynonenal. All the compounds tested form a new class of acyl-CoA esters, 4-hydroxy-4-phosphoacyl-CoAs, characterized by liquid chromatography-tandem mass spectrometry, accurate mass spectrometry, and 31 P-NMR. All 4-hydroxyacids with five or more carbons are metabolized by two new pathways. The first and major pathway, which involves 4-hydroxy-4-phosphoacylCoAs, leads in six steps to the isomerization of 4-hydroxyacylCoA to 3-hydroxyacyl-CoAs. The latter are intermediates of physiological ␤-oxidation. The second and minor pathway involves a sequence of ␤-oxidation, ␣-oxidation, and ␤-oxidation steps. In mice deficient in succinic semialdehyde dehydrogenase, high plasma concentrations of 4-hydroxybutyrate result in high concentrations of 4-hydroxy-4-phospho-butyryl-CoA in brain and liver. The high concentration of 4-hydroxy-4-phospho-butyryl-CoA may be related to the cerebral dysfunction of subjects ingesting 4-hydroxybutyrate and to the mental retardation of patients with 4-hydroxybutyric aciduria. Our data illustrate the potential of the combination of metabolomics and mass isotopomer analysis for pathway discovery.4-Hydroxy-n-acids are involved in different areas of mammalian metabolism. Some unsaturated 4-hydroxyacids are derived from 4-hydroxynonenal and 4-hydroxyhexenal, which are products of lipid peroxidation (1). The metabolism of 4-hydroxynonenal has been extensively studied, especially its conjugation with glutathione (2), covalent modification of proteins (3, 4), and conversion to 4-hydroxynonenoate, 4-hydroxynonanoate and 1,4-dihydroxynonene, as well as its role in inflammatory processes (1, 5-11). However, the catabolism of its carbon skeleton has not been unraveled. The four-carbon 4-hydroxybutyrate is a physiological neurotransmitter derived from ␥-aminobutyrate. Humans with inborn disorder of succinic semialdehyde dehydrogenase have high 4-hydroxybutyrate concentrations in body fluids, mental retardation, and seizures (12). 4-Hydroxybutyrate is also a drug of abuse that impairs the capacity to exercise judgment for unknown reasons. 4-Hydroxybutyrate is used for the treatment of narcolepsy (13). Its known metabolism (14, 15) proceeds via oxidation to succinic semialdehyde and then to succinate, an intermediate of the citric acid cycle. The five-carbon 4-hydroxypentanoate is also a drug of abuse (16). The calcium salt of a compound closely related to 4-hydroxypentanoate, levulinate (4-ketopentanoate, 4-ketovalerate), is used as an oral or intravenous source of calcium in humans.We conducted a study on the catabolism of C 4 to C 11 4-hydroxyacids in perfused rat livers using a combination of metabolomics (17,18) and mass isotopomer analysis 2 (19)....

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Section: ⅐Gmentioning

confidence: 55%

Section: -Phosphoacyl-coas In 4-hydroxyacid Metabolismmentioning

confidence: 99%

Section: -Phosphoacyl-coas In 4-hydroxyacid Metabolismmentioning

confidence: 99%

mentioning

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Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

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“…Dazu gehört z.B. der Abbau oxidativ modifizierter Eiweisse und der Metabolismus aldehydischer LPO-Produkte wie HNE und Malondialdehyd (MDA) [4,33,34,37,38,39,40,41,42] (Abb. 1).…”

Section: Introductionunclassified

Reduktion prooxidativer und Stärkung antioxidativer Prozesse - ein verbindendes Element der Kneipp'schen Therapie

Brenke¹,

Siems²

2013

Schweiz Z Ganzheitsmed

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Die Kneipp'schen Therapieverfahren und damit zentrale Inhalte der klassischen Naturheilverfahren zeichnen sich durch ein breites Wirkungsspektrum aus. Es ist naheliegend, dass diesen Verfahren auch gemeinsame Wirkungsmechanismen auf der Basis ubiquitärer Substanzen und Reaktionsmechanismen zugrunde liegen. Hier wurden die Wirkungen von reaktiven Sauerstoffspezies (ROS), von Lipid peroxidations(LPO)-Produkten und von antioxidativen Schutzmechanismen untersucht. Die Bilanz von prooxidativen und antioxidativen Prozessen, die das Mass für einen oxidativen Stress angibt, hat eine immense Auswirkung auf Gesundheit, Krankheit, Wohlbefinden und Leistungsfähigkeit. Die Übersicht über Resultate zu allen fünf Säulen der Kneipp-Therapie - Hydrotherapie, Phytotherapie, Ernährungstherapie, Bewegungstherapie und Ordnungstherapie - liefert klare Hinweise auf die bessere Bewältigung von oxidativem Stress durch die Kneipp'schen Therapieformen. Es wird deutlich aufgezeigt, dass eine verminderte Bildung freier Radikale und/oder deren bessere Bewältigung ein verbindendes Element der klassischen Naturheilverfahren ist.

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Reactive species and mitochondrial dysfunction: Mechanistic significance of 4‐hydroxynonenal

Roede

Jones

2010

Environ and Mol Mutagen

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Mitochondrial dysfunction is a global term used in the context of “unhealthy” mitochondria. In practical terms, mitochondria are extremely complex and highly adaptive in structure, chemical and enzymatic composition, subcellular distribution and functional interaction with other components of cells. Consequently, altered mitochondrial properties that are used in experimental studies as measures of mitochondrial dysfunction often provide little or no distinction between adaptive and maladaptive changes. This is especially a problem in terms of generation of oxidant species by mitochondria, wherein increased generation of superoxide anion radical false(O2−⋅false) or hydrogen peroxide (H2O2) is often considered synonymously with mitochondrial dysfunction. However, these oxidative species are signaling molecules in normal physiology so that a change in production or abundance is not a good criterion for mitochondrial dysfunction. In this review, we consider generation of reactive electrophiles and consequent modification of mitochondrial proteins as a means to define mitochondrial dysfunction. Accumulated evidence indicates that 4-hydroxynonenal (HNE) modification of proteins reflects mitochondrial dysfunction and provides an operational criterion for experimental definition of mitochondrial dysfunction. Improved means to detect and quantify mitochondrial HNE-protein adduct formation could allow its use for environmental health risk assessment. Furthermore, application of improved mass spectrometry-based proteomic methods will lead to further understanding of the critical targets contributing to disease risk.

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Metabolism of 4-Hydroxynonenal, a Cytotoxic Lipid Peroxidation Product, in Thymocytes as an Effective Secondary Antioxidative Defense Mechanism

Cited by 22 publications

References 0 publications

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Reduktion prooxidativer und Stärkung antioxidativer Prozesse - ein verbindendes Element der Kneipp'schen Therapie

Reactive species and mitochondrial dysfunction: Mechanistic significance of 4‐hydroxynonenal

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