Covalent modification of cytochrome c by reactive metabolites of furan

Chemical Research in Toxicology
Martin B PhillipsL A Peterson

Abstract

Metabolism of the hepatotoxicant furan leads to protein adduct formation in the target organ. The initial bioactivation step involves cytochrome P450-catalyzed oxidation of furan, generating cis-2-butene-1,4-dial (BDA). BDA reacts with lysine to form pyrrolin-2-one adducts. Metabolic studies indicate that BDA also reacts with glutathione (GSH) to generate 2-(S-glutathionyl)butanedial (GSH-BDA), which then reacts with lysine to form GSH-BDA-lysine cross-links. To explore the relative reactivity of these two reactive intermediates, cytochrome c was reacted with BDA in the presence and absence of GSH. As judged by MALDI-TOF mass spectrometry, BDA reacts extensively with cytochrome c to form adducts that add 66 Da to the protein, consistent with the formation of pyrrolinone adducts. Addition of GSH to the reaction mixture reduced the overall extent of adduct formation. The mass of the adducted protein was shifted by 355 Da as expected for GSH-BDA-protein cross-link formation. LC-MS/MS analysis of the tryptic digests of the alkylated protein indicated that the majority of adducts occurred on lysine residues, with BDA reacting less selectively than GSH-BDA. Both types of adducts may contribute to the toxic effects of furan.

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Citations

Feb 5, 2016·Chemical Research in Toxicology·Xiucai GuoJiang Zheng
Jan 21, 2015·Journal of Mass Spectrometry : JMS·Andreas Schinkovitz, Pascal Richomme
Apr 20, 2016·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Hui LiJiang Zheng
Apr 12, 2017·Organic & Biomolecular Chemistry·Xiaodong Yang, Rulong Yan
Apr 23, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Leah A GatesLisa A Peterson
Oct 25, 2017·EFSA Journal·UNKNOWN EFSA Panel on Contaminants in the Food Chain (CONTAM)Heather Wallace
Sep 6, 2020·Chembiochem : a European Journal of Chemical Biology·Penthip Muangkaew, Tirayut Vilaivan
May 21, 2014·Chemical Research in Toxicology·Liudmyla K SviatenkoJerzy Leszczynski
Jul 8, 2020·Chemical Research in Toxicology·Lei ZhangJun Sun
Oct 5, 2021·The Journal of Organic Chemistry·Debabrata MaitiSuman De Sarkar

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