Electron impact mass spectrometric analysis of mercapturic acid methyl esters. Fragmentation of mercapturic acid methyl esters according to ‘retro-Michael’ reactions

Onkenhout, W.; Vermeulen, Nico; Luijten, W. C. M. M.; Jong, H. J. De

doi:10.1002/bms.1200101107

Cited by 18 publications

(3 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The concept of diagnostic fragment ions as a tool to screen for adducts was previously recognized by Onkenhout et al 49 By examination of a series of synthetically prepared mercapturic acid methyl esters, three diagnostic ions from the N-acetylcysteine methyl ester part of the mercapturic acids were identified. These ions may be useful for the analysis of mercapturic acids of unknown masses.…”

Section: ' Discussionmentioning

confidence: 99%

Application of CYP102A1M11H as a Tool for the Generation of Protein Adducts of Reactive Drug Metabolites

Boerma

Vermeulen

Commandeur

2011

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

Covalent binding of reactive metabolites (RMs) to proteins is considered to be one of the important mechanisms by which drugs can cause tissue damage. To facilitate the study of drug-protein adducts, we developed a potentially generic method for producing high levels of covalently modified proteins. A highly active drug metabolizing P450 BM3 mutant (CYP102A1M11H) is used for drug bioactivation. Because of its His-tag, CYP102A1M11H is easily removed by nickel affinity chromatography, facilitating subsequent characterization of the modified target protein. The applicability of our procedure is demonstrated by the trapping of RMs of acetaminophen (APAP), clozapine (CLOZ), and troglitazone (TGZ) with human glutathione-S-transferase P1-1 (hGST P1-1) as the model target protein. Tryptic digests of hGST P1-1 were subjected to analysis by LC-MS/MS and modified peptides identified by the comparative analysis of tryptic peptides of adducted and nonadducted hGST P1-1. Characteristic MS/MS ions of drug-modified peptides were identified by first searching for expected adduct-masses. Unanticipated drug-peptide adducts were subsequently identified in an unbiased manner by screening for diagnostic MS/MS ions of modified peptides. Reactive intermediates of APAP and CLOZ adducted to cysteine-47 and mass shifts corresponded to the alkylation of N-acetyl-p-benzoquinone imine (NAPQI) and the CLOZ nitrenium ion, respectively. Adduction of TGZ appeared more complex, yielding three different types of adducts to cysteine-47, two adducts to cysteine-14, and a single adduct to cysteine-101. Together, these findings show that P450 BM3 mutants with high capacity to activate drugs into relevant RMs can be employed to produce protein adducts to study the nucleophilic selectivity of highly reactive electrophiles.

show abstract

Section: ' Discussionmentioning

confidence: 99%

Application of CYP102A1M11H as a Tool for the Generation of Protein Adducts of Reactive Drug Metabolites

Boerma

Vermeulen

Commandeur

2011

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The mass spectrum had a base peak at m/z 104, [CrHsCH-CHa] +, and fragment ions at m/z 222 (M+ -59), m/z 177 (M+ -104) and m/z 91. In El-mass spectra of the mercapturic acids, several common and characteristic fragmentation reactions involving the N-acetylcysteine-ME part of the molecular ionic species were identified (Onkenhout et al 1983); fragment ions at m/z 176, [C6H10NO3S]+; m/z 59, CH3CONH2 and/or CH3OCO. ; m/z 91, the tropylium ion.…”

Section: Discussionmentioning

confidence: 99%

Detection and measurement of S-benzyl-N-acetylcysteine in urine of toluene sniffers using capillary gas chromatography

et al. 1993

View full text Add to dashboard Cite

We examined the urinary excretion of S-benzyl-N-acetylcysteine (SBAC) of toluene sniffers using capillary gas chromatography. SBAC was extracted from 10 ml urine with chloroform and backextracted into 1 M sodium bicarbonate solution. After acidification, the aqueous solution was reextracted with ethyl acetate, and then derivatized to its methyl ester (ME). The peak appearing in the gas chromatogram was identified as SBAC-ME by mass spectrometry. The calibration curve was constructed by plotting the peak height ratio of SBAC-ME and internal standard (S-phenethyl-N-acetylcysteine)-ME against analyte concentration using 10 ml toluene unexposed urine. It showed good linearity over the range of 0.05-3.0 mg/l (r = 0.99). We have applied this technique to urine samples from toluene sniffers. SBAC was detected in all urinary samples of sniffers (n = 30, 0.11-47.13 mg/l), but not at all in the urine of toluene unexposed subjects (n = 60). These results prove that SBAC is also formed from toluene by human metabolism, and detection of SBAC is considered a useful marker for inhalation of toluene.

show abstract

“…and m/z 88 [C 3 H 6 NO 2 ] + [62]. All those characteristic key ions of methyl derivatives of MAs were observed for halothane-derived mercapturic acid as well; m/z 88, 144, and 176.…”

Section: Halothane and Isofluranementioning

confidence: 91%

Analyses of representative biomarkers of exposure and effect by chromatographic, mass spectrometric, and nuclear magnetic resonance techniques: Method development and application in life sciences

Orhan¹

2007

J of Separation Science

View full text Add to dashboard Cite

Biomarkers are essential tools in monitoring studies, which include environmental monitoring, biological monitoring, biological effect monitoring, and health surveillance, as well as drug development processes. Their discovery, validation, and analysis require highly sensitive and selective analytical technologies. In this regard, gas and liquid chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy have facilitated great achievements in all these areas. In addition and closely related to biomarkers, the ongoing developments in these techniques promise a better understanding of the nature and mechanisms of toxic effects originating from various chemical, biological, or physical sources. This Review compiles studies performed on selected biomarkers with respect to both method development and application. Section 1 summarizes the concept of biomarkers; their application in various industrial/occupational, agricultural, drug developmental, and medical/clinical platforms. This section also focuses on biotransformation studies in close relation to biomarker discovery and validation, and on major techniques utilized in this area. In Section 2, biotransformation of volatile anesthetics in humans with a focus on mercapturic acid derivatives as potential biomarkers of effect is reviewed. The use of GC-ECD, GC/MS, and 19F-NMR in these studies is described. Section 3 focuses on the analysis of aldehydic lipid peroxidation degradation products by GC-ECD in mammalian cells in which oxidative stress induced chemically, and in humans after various challenges; anesthetic exposure, ischemia-reperfusion, and controlled endurance exercise. In Section 4, method development for protein and DNA oxidation products by LC-tandem MS and its application in mammalian cells and in humans are summarized. Possibilities, limitations, and future perspectives are discussed in Section 5.

show abstract

Electron impact mass spectrometric analysis of mercapturic acid methyl esters. Fragmentation of mercapturic acid methyl esters according to ‘retro-Michael’ reactions

Cited by 18 publications

References 18 publications

Application of CYP102A1M11H as a Tool for the Generation of Protein Adducts of Reactive Drug Metabolites

Application of CYP102A1M11H as a Tool for the Generation of Protein Adducts of Reactive Drug Metabolites

Detection and measurement of S-benzyl-N-acetylcysteine in urine of toluene sniffers using capillary gas chromatography

Analyses of representative biomarkers of exposure and effect by chromatographic, mass spectrometric, and nuclear magnetic resonance techniques: Method development and application in life sciences

Contact Info

Product

Resources

About