Identification of Novel Urinary Metabolites of the Lipid Peroxidation Product 4-Hydroxy-2-nonenal in Rats

Alary, J.; Debrauwer, Laurent; Fernandez, Yvette; Paris, Alain; Cravedi, Jean‐Pierre; Dolo, Laurence; Rao, Dinesh; Bories, Georges

doi:10.1021/tx980068g

Cited by 41 publications

(43 citation statements)

References 14 publications

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“…It is important to bear in mind that as well as reacting with macromolecules, free aldehydes may be metabolized and detoxified, so analysis of the metabolite may represent a good approach to detecting formation of the aldehyde in vivo. It is well known that HNE can be detoxified by conjugation to glutathione, catalysed by glutathione-S-transferases [94], and metabolized further to yield 1,4-dihydroxynonane-mercapturic acid, which can be detected in the urine together with other metabolites [95]. Trans,trans-2,4-decadienal (tt-DDE), a lipid peroxidation product of linoleic acid, can be oxidized to the two metabolites 2,4-decadienoic acid and cysteine-conjugated 2,4-decadien-1-ol.…”

Section: Analysis Of Free Aldehydic Oxidation Products and Their Metamentioning

confidence: 99%

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Sousa

Pitt

Spickett

2017

Free Radical Biology and Medicine

145

105

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The process of lipid oxidation generates a diverse array of small aldehydes and carbonyl-containing compounds, which may occur in free form or esterified within phospholipids and cholesterol esters. These aldehydes mostly result from fragmentation of fatty acyl chains following radical oxidation, and the products can be subdivided into alkanals, alkenals (usually D,β-unsaturated), γ-substituted alkenals and bis-aldehydes.Isolevuglandins are non-fragmented di-carbonyl compounds derived from H 2 -isoprostanes, and oxidation of the ω-3-fatty acid docosahexenoic acid yield analogous 22 carbon neuroketals. Non-radical oxidation by hypochlorous acid can generate D-chlorofatty aldehydes from plasmenyl phospholipids. Most of these compounds are reactive and have generally been considered as toxic products of a deleterious process. The reactivity is especially high for the D,β-unsaturated alkenals, such as acrolein and crotonaldehyde, and for γ-substituted alkenals, of which 4-hydroxy-2-nonenal and 4-oxo-2-nonenal are best Page | 2 known. Nevertheless, in recent years several previously neglected aldehydes have been investigated and also found to have significant reactivity and biological effects; notable examples are 4-hydroxy-2-hexenal and 4-hydroxy-dodecadienal. This has led to substantial interest in the biological effects of all of these lipid oxidation products and their roles in disease, including proposals that HNE is a second messenger or signalling molecule.However, it is becoming clear that many of the effects elicited by these compounds relate to their propensity for forming adducts with nucleophilic groups on proteins, DNA and specific phospholipids. This emphasizes the need for good analytical methods, not just for free lipid oxidation products but also for the resulting adducts with biomolecules. The most informative methods are those utilizing HPLC separations and mass spectrometry, although analysis of the wide variety of possible adducts is very challenging. Nevertheless, evidence for the occurrence of lipid-derived aldehyde adducts in biological and clinical samples is building, and offers an exciting area of future research. AbbreviationsAcr-dG, 1,N2-propanodeoxyguanosine; AGEs, advanced glycation end-product; ALEs, advanced lipoxidation end product; ApoB100, apolipoprotein B100; ApoE, apolipoprotein E; ARP, aldehyde reactive probe; AspN, endoproteinase AspN (flavastacin); βLG, β-lactoglobulin; BHZ, biotin hydrazide; BN-PAGE, blue native polyacrylamide gel

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Section: Analysis Of Free Aldehydic Oxidation Products and Their Metamentioning

confidence: 99%

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Sousa

Pitt

Spickett

2017

Free Radical Biology and Medicine

145

105

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“…As the concentration of GSTs cannot exceed the concentration of nucleophiles in the cell, it is the capacity of GSTs to stabilize the strongly nucleophilic GSH thiolate and bind and conjugate hydrophobic molecules that provide this overcapacity. In evolutionary terms, products of oxidative stress could be particularly important since enzyme efficiencies close to the diffusion limit have been observed [e.g., hydroxyalkenals and certain GSTs (Jensson et al, 1986)], and humans actually excrete 5 g of the mercapturic acid of 4-hydroxynonenal per day (corresponding to 15 nmol) (Alary et al, 1998).…”

Section: A Tremendous Overcapacity In Terms Of Glutathione Transferasmentioning

confidence: 99%

Reactive Intermediates and The Dynamics of Glutathione Transferases

Rinaldi

Eliasson²,

Swedmark³

et al. 2002

Drug Metab Dispos

123

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ABSTRACT:Reactive intermediates are a continuous burden in biology and several defense mechanisms have evolved. Here we focus on the functions of glutathione transferases (GSTs) with the aim to discuss the quantitative aspects of defense against reactive intermediates. Humans excrete approximately 0.1 mmol of thioether conjugates per day. As the amount of GST active sites in liver is Ϸ0.5 mmol, it appears that glutathione transferase catalysts are present in tremendous excess. In fact, the known catalytic properties of GSTs reveal that the enzymes can empty the liver glutathione (GSH) pool in a matter of seconds when provided with a suitable substrate. However, based on the urinary output of conjugates (or derivatives thereof), individual GSTs turn over (i.e., catalyze a single reaction) only once every few days. Glutathione transferase overcapacity reflects the fact that there is a linear relation between GST enzyme amount and protection level (provided that GSH is not depleted). Put in a different perspective, a few reactive molecules will always escape conjugation and reach cellular targets. It is therefore not surprising that signaling systems sensing reactive intermediates have evolved resulting in the increase of GSH and GST levels. Precisely for this reason, more moderately reactive electrophiles (Michael acceptors) are receiving growing interest due to their anticarcinogenic properties. Another putative regulatory mechanism involves direct activation of microsomal GST1 by thiol-reactive electrophiles through cysteine 49. The toxicological significance of low levels of reactive intermediates are of interest also in drug development, and here we discuss the use of microsomal GST1 activation as a surrogate detection marker.

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“…These hydrophilic analytes are well ionized by electrospray. However, the compound-specific methods do not permit screening for compounds with unknown structures such as metabolites, and synthetic reference materials are necessary to develop a sensitive MRM method in complex matrices [5][6][7][8]. Metabolite stan-dards are rarely available and screening for unknowns in the full scan mode is difficult owing to the limited sensitivity and specificity in complex matrices.…”

mentioning

confidence: 99%

Rapid detection and identification of N-acetyl-L-cysteine thioethers using constant neutral loss and theoretical multiple reaction monitoring combined with enhanced product-ion scans on a linear ion trap mass spectrometer

Scholz

Dekant

Völkel

et al. 2005

J. Am. Soc. Mass Spectrom.

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A sensitive and specific liquid chromatography-mass spectrometry (LC-MS) method based on the combination of constant neutral loss scans (CNL) with product ion scans was developed on a linear ion trap. The method is applicable for the detection and identification of analytes with identical chemical substructures (such as conjugates of xenobiotics formed in biological systems) which give common CNLs. A specific CNL was observed for thioethers of N-acetyl-L-cysteine (mercapturic acids, MA) by LC-MS/MS. MS and HPLC parameters were optimized with 16 MAs available as reference compounds. All of these provided a CNL of 129 Da in the negative-ion mode. To assess sensitivity, a multiple reaction monitoring (MRM) mode with 251 theoretical transitions using the CNL of 129 Da combined with a product ion scan (IDA thMRM) was compared with CNL combined with a product ion scan (IDA CNL). An information-dependent acquisition (IDA) uses a survey scan such as MRM (multiple reaction monitoring) to generate "informations" and starting a second acquisition experiment such as a product ion scan using these "informations." Th-MRM means calculated transitions and not transitions generated from an available standard in the tuning mode. The product ion spectra provide additional information on the chemical structure of the unknown analytes. All MA standards were spiked in low concentrations to rat urines and were detected with both methods with LODs ranging from 60 pmol/mL to 1.63 nmol/mL with IDA thMRM. The expected product ion spectra were observed in urine. Application of this screening method to biological samples indicated the presence of a number of MAs in urine of unexposed rats, and resulted in the identification of 1,4-dihydroxynonene mercapturic acid as one of these MAs by negative and positive product ion spectra. These results show that the developed methods have a high potential to serve as both a prescreen to detect unknown MAs and to identify these analytes in complex matrix. (J Am Soc Mass Spectrom 2005, 16, 1976 -1984

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Identification of Novel Urinary Metabolites of the Lipid Peroxidation Product 4-Hydroxy-2-nonenal in Rats

Cited by 41 publications

References 14 publications

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Reactive Intermediates and The Dynamics of Glutathione Transferases

Rapid detection and identification of N-acetyl-L-cysteine thioethers using constant neutral loss and theoretical multiple reaction monitoring combined with enhanced product-ion scans on a linear ion trap mass spectrometer

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