Site-specific arylation of rat glutathione s-transferase A1 and A2 by bromobenzene metabolites in vivo.

Site-specific arylation of rat glutathione s-transferase A1 and A2 by bromobenzene metabolites in vivo. Research Abstract Details 

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Site-specific arylation of rat glutathione s-transferase A1 and A2 by bromobenzene metabolites in vivo. Abstract Text:

Yakov M Koen,Weimin Yue,Nadezhda A Galeva,Todd D Williams,Robert P Hanzlik,

The hepatotoxicity of bromobenzene (BB) derives from its reactive metabolites (epoxides and quinones), which arylate cellular proteins. Application of proteomic methods to liver proteins from rats treated with a hepatotoxic dose of [14C]-BB has identified more than 40 target proteins, but no adducted peptides have yet been observed. Because such proteins are known to contain bromophenyl- and bromodihydroxyphenyl derivatives of cysteine, histidine, and lysine, the failure to observe modified peptides has been attributed to the low level of total covalent binding and to the "dilution" effect of multiple metabolites reacting at multiple sites on multiple proteins. In this work glutathione S-transferase (GST), a well-known and abundant BB-target protein, was isolated from liver cytosol of rats treated with 14C-BB by use of a glutathione (GSH)-agarose affinity column and further resolved by reverse-phase high-performance liquid chromatography (HPLC) into subunits M1, M2, A1, A2 and A3. The subunits were identified by a combination of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), whole-molecule mass spectrometry, and peptide mass mapping and found to contain radioactivity corresponding to 0.01-0.05 adduct per molecule of protein. Examination of tryptic digests of these subunits by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) and electrospray ionization mass spectrometry (ESI-MS) failed to reveal any apparent adducted peptides despite observed sequence coverages up to 87%. However, use of HPLC-linear ion-trap quadrupole Fourier transform mass spectrometry (LTQ-FTMS) to search for predicted modified tryptic peptides revealed peaks corresponding, with a high degree of mass accuracy, to a bromobenzoquinone adduct of peptide 89-119 in both GSTA1 and A2. The identity of these adducts and their location at Cys-111 was confirmed by tandem mass spectrometry (MS-MS). No evidence for the presence of any putative BB-adducts in GST M1, M2, or A3 was obtained. This work highlights the challenges involved in the unambiguous identification of reactive metabolite adducts formed in vivo.

Site-specific arylation of rat glutathione s-transferase A1 and A2 by bromobenzene metabolites in vivo. Publishing Authors By Initials

YM Koen,W Yue,NA Galeva,TD Williams,RP Hanzlik,

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Site-specific arylation of rat glutathione s-transferase A1 and A2 by bromobenzene metabolites in vivo. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Chemical research in toxicology

VOLUME: 19

Page Numbers: 1426-34

Journal Abbreviation: Chem. Res. Toxicol.

ISSN: 0893-228X

DAY: 3

MONTH: Nov

YEAR: 2006

Site-specific arylation of rat glutathione s-transferase A1 and A2 by bromobenzene metabolites in vivo. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8807448

Site-specific arylation of rat glutathione s-transferase A1 and A2 by bromobenzene metabolites in vivo. Keywords Mesh Terms:

KEYWORDS: Spectrometry, Mass, Matrix-Assisted Lase

MESH TERMS: enzymology

Chemical & Substance for Abstract: Site-specific arylation of rat glutathione s-transferase A1 and A2 by bromobenzene metabolites in vivo. Information

Substance Name: glutathione S-transferase alpha

Registry Number: EC 2.5.1.18

Grant and Affiliation Information for Site-specific arylation of rat glutathione s-transferase A1 and A2 by bromobenzene metabolites in vivo.

AFFILIATION: Department of Medicinal Chemistry and Mass Spectrometry Laboratory, University of Kansas, Lawrence, Kansas 66045, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: GM-27184

ACRONYM: GM

MEDLINETA: Chem Res Toxicol

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