Fate of 4-hydroxynonenal in vivo: disposition and metabolic pathways

Alary, J.; Guéraud, Françoise; Cravedi, Jean‐Pierre

doi:10.1016/s0098-2997(03)00012-8

Cited by 128 publications

(113 citation statements)

References 25 publications

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“…One group comes from the formation of mercapturic acid from (a) DHN-GSH, which originates from the conjugation of HNE with GSH by glutathione S-transferases and the subsequent reduction of the aldehyde by a member of the aldo-keto reductase superfamily; (b) the lactone of HNA-GSH (HNA-lactone-GSH), which originates from the conjugation of HNE followed by the oxidation of the aldehyde by aldehyde dehydrogenase; and (c) HNA-GSH, which originates from the hydrolysis of the corresponding lactone. The other group consists of metabolites issuing from the -hydroxylation of HNA or HNA-lactone by cytochromes P450 4A, followed eventually, in the case of -oxidized HNA-lactone, by conjugation with GSH and subsequent mercapturic acid formation (153 ). The metabolism of HNE-protein adducts, involving probably the proteasome pathway, might take too long for the metabolites to be excreted in urine within 24 or 48 h, particularly because HNE has been shown to reduce some of the proteolytic activities of the proteasome (154 ).…”

Section: Metabolism Of Oxidized Biomoleculesmentioning

confidence: 99%

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Biomarkers of Oxidative Damage in Human Disease

et al. 2006

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Oxidative/nitrosative stress, a pervasive condition of increased amounts of reactive oxygen/nitrogen species, is now recognized to be a prominent feature of many acute and chronic diseases and even of the normal aging process. However, definitive evidence for this association has often been lacking because of recognized shortcomings with biomarkers and/or methods available to assess oxidative stress status in humans. Emphasis is now being placed on biomarkers of oxidative stress, which are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic intervention. To be a predictor of disease, a biomarker must be validated. Validation criteria include intrinsic qualities such as specificity, sensitivity, degree of inter-and intraindividual variability, and knowledge of the confounding and modifying factors. In addition, characteristics of the sampling and analytical procedures are of relevance, including constraints and noninvasiveness of sampling, stability of potential biomarkers, and the simplicity, sensitivity, specificity, and speed of the analytical method. Here we discuss some of the more commonly used biomarkers of oxidative/nitrosative damage and include selected examples of human studies.

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Section: Metabolism Of Oxidized Biomoleculesmentioning

confidence: 99%

“…This and the above factors considered together imply that the metabolism of endogenous HNE likely Clinical Chemistry 52, No. 4,2006 shows quantitative differences dependent on the site of generation and, especially, on the ratio of free GSH to reactive proteins (153 ).…”

Section: Metabolism Of Oxidized Biomoleculesmentioning

confidence: 99%

Biomarkers of Oxidative Damage in Human Disease

et al. 2006

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“…Once formed, HNE is rapidly degraded by three major reactions: reduction to 1,4-dihydroxy-2-nonene by alcohol dehydrogenases (172), oxidation to 4-hydroxy-2-nonenoic acid by aldehyde dehydrogenase (173)(174)(175), or formation of the glutathione-conjugate (GS-HNE) catalyzed by glutathione-S-transferases as shown in equation <2>. The majority of HNE is metabolized through forming GS-HNE (172).…”

Section: A Hne: Production Reaction and Eliminationmentioning

confidence: 99%

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Forman

Fukuto

Miller

et al. 2008

Archives of Biochemistry and Biophysics

219

165

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During the past several years, major advances have been made in understanding how reactive oxygen species (ROS) and nitrogen species (RNS) participate in signal transduction. Identification of the specific targets and the chemical reactions involved still remains to be resolved with many of the signaling pathways in which the involvement of reactive species has been determined. Our understanding is that ROS and RNS have second messenger roles. While cysteine residues in the thiolate (ionized) form found in several classes of signaling proteins can be specific targets for reaction with H 2 O 2 and RNS, better understanding of the chemistry, particularly kinetics, suggests that for many signaling events in which ROS and RNS participate, enzymatic catalysis is more likely to be involved than non-enzymatic reaction. Due to increased interest in how oxidation products, particularly lipid peroxidation products, also are involved with signaling, a review of signaling by 4-hydroxy-2-nonenal (HNE) is included. This article focuses on the chemistry of signaling by ROS, RNS, and HNE and will describe reactions with selected target proteins as representatives of the mechanisms rather attempt to comprehensively review the many signaling pathways in which the reactive species are involved. Keywords signaling; glutathione; thioredoxin; oxidants; reactive oxygen species; thiols; peroxide; nitric oxide; peroxynitrite; 4-hydroxynonenal; cysteine; hydrogen peroxide; protein tyrosine phosphatase; reactive nitrogen species; eNOS; iNOS; nNOS; soluble guanylate cyclase; cGMP; tyrosine nitration; fatty acid nitration; NO-heme; NO-metal complexes; nitrite; protein kinase C; ERK; JNK; p38MAPK; tyrosine kinase receptors; calcium OVERVIEW OF SIGNALING BY REACTIVE SPECIESUnderstanding of the roles of reactive oxygen species (ROS), reactive nitrogen species (RNS) and the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE) in signaling has evolved rapidly during the last decade. This has been markedly helped by identification of the specific targets in signaling pathways. In previous reviews, we defined how ROS, H 2 O 2 in particular,

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“…1. A number of studies have examined HNE and its metabolites in vivo (10,(15)(16)(17)(18) and have demonstrated the formation of the MA conjugates HNE-MA, DHN-MA, HNA-MA, and HNA-MA lactone in vivo (10). In addition, histidine-1,4-dihydroxynonane (His-DHN) and His-HNA have been found in the urine of obese Zucker rats, a model of metabolic syndrome (19).…”

Section: Lipid Peroxidation (Lpo)mentioning

confidence: 99%

Mercapturic Acid Conjugates of 4-Hydroxy-2-nonenal and 4-Oxo-2-nonenal Metabolites Are in Vivo Markers of Oxidative Stress

Kuiper

Miranda

Sowell

et al. 2008

Journal of Biological Chemistry

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Oxidative stress-induced lipid peroxidation leads to the formation of cytotoxic and genotoxic 2-alkenals, such as 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE). Lipid-derived reactive aldehydes are subject to phase-2 metabolism and are predominantly found as mercapturic acid (MA) conjugates in urine. This study shows evidence for the in vivo formation of ONE and its phase-1 metabolites, 4-oxo-2-nonen-1-ol (ONO) and 4-oxo-2-nonenoic acid (ONA). We have detected the MA conjugates of HNE, 1,4-dihydroxy-2-nonene (DHN), 4-hydroxy-2-nonenoic acid (HNA), the lactone of HNA, ONE, ONO, and ONA in rat urine by liquid chromatography-tandem mass spectrometry comparison with synthetic standards prepared in our laboratory. CCl 4 treatment of rats, a widely accepted animal model of acute oxidative stress, resulted in a significant increase in the urinary levels of DHN-MA, HNA-MA lactone, ONE-MA, and ONA-MA. Our data suggest that conjugates of HNE and ONE metabolites have value as markers of in vivo oxidative stress and lipid peroxidation. Lipid peroxidation (LPO)2 products are breakdown products of fatty acids formed under conditions of oxidative stress. 4-Hydroxy-2-nonenal (HNE) is a well established LPO product that has been shown to contribute to the development and progression of age-related diseases such as Alzheimer and atherosclerosis (1-4) in addition to being cytotoxic and genotoxic (5, 6). The mechanism of formation for HNE from linoleic acid via 4-hydroperoxy-2-nonenal (HPNE) has been previously demonstrated (7). Once HNE is formed, it can be further metabolized by cytochrome P450, aldehyde dehydrogenase, aldo-keto reductase (AKR), and conjugated by glutathione S-transferase (GST). Certain isoforms of murine and human P450s (8) and aldehyde dehydrogenase (9) can catalyze the oxidation of HNE to 4-hydroxy-2-nonenoic acid (HNA). When conjugated, HNA can undergo spontaneous intramolecular condensation, resulting in lactone formation (10). Aldo-keto reductase 1B1 has been shown to reduce HNE to form 1,4-dihydroxy-2-nonene (DHN) (11). Glutathione (GSH) can form conjugates with HNE and other LPO products (6) via a Michael-type addition mediated by . The GSH can then be further metabolized in the liver and in the kidney to form mercapturic acid (MA), resulting in the conjugates shown in Fig. 1. A number of studies have examined HNE and its metabolites in vivo (10,(15)(16)(17)(18) and have demonstrated the formation of the MA conjugates HNE-MA, DHN-MA, HNA-MA, and HNA-MA lactone in vivo (10). In addition, histidine-1,4-dihydroxynonane (His-DHN) and His-HNA have been found in the urine of obese Zucker rats, a model of metabolic syndrome (19).Not only can HPNE break down into HNE, but it can also form 4-oxo-2-nonenal (ONE) as shown in vitro (20) and in cultured cells (21). ONE can be reduced at the C-4 position by carbonyl reductase to form HNE (22), but it can also be reduced at the C-1 position by aldo-keto reductase to form 4-oxo-2-nonen-1-ol (ONO) (21,23,24) or oxidized by aldehyde dehydrogenase (human aldehyde dehy...

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Fate of 4-hydroxynonenal in vivo: disposition and metabolic pathways

Cited by 128 publications

References 25 publications

Biomarkers of Oxidative Damage in Human Disease

Biomarkers of Oxidative Damage in Human Disease

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Mercapturic Acid Conjugates of 4-Hydroxy-2-nonenal and 4-Oxo-2-nonenal Metabolites Are in Vivo Markers of Oxidative Stress

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