Mass Spectrometric Characterization of an Acid-Labile Adduct Formed with 2-Amino-1-methyl-6-phenylimidazo[4,5- b ]pyridine and Albumin in Humans
- Univ. of Minnesota, Minneapolis, MN (United States). Masonic Cancer Center and Dept. of Medicinal Chemistry
- Univ. of Minnesota, Minneapolis, MN (United States). Masonic Cancer Center
- Wuhan Polytechnic Univ., Wuhan (China). School of Food Science and Engineering
- Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biosciences and Biotechnology Division, Center for Accelerator Mass Spectrometry
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a carcinogenic heterocyclic aromatic amine formed during the high-temperature cooking of meats. The cytochrome P450-mediated N-hydroxylation of the exocyclic amine group of PhIP produces 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-$$b$$]pyridine, an electrophilic metabolite that forms adducts with DNA and proteins. Previous studies conducted by our laboratory showed that the reaction of N-oxidized PhIP metabolites with human albumin in vitro primarily occurs at the Cys34 residue, to produce an acid-labile linked sulfinamide adduct. On the basis of these findings, we developed a sensitive ultraperformance liquid chromatography–mass spectrometry method to measure acid-labile albumin–PhIP adducts in human volunteers administered a dietary-relevant dose of 14C-labeled PhIP [Dingley, K. H., et al. (1999) Cancer Epidemiol., Biomarkers Prev. 8, 507–512]. Mild acid treatment of albumin (0.1 N HCl, 37 °C for 1 h) or proteolytic digestion with Pronase [50 mM ammonium bicarbonate buffer (pH 8.5) at 37 °C for 18 h] released similar amounts of covalently bound PhIP, which was characterized by multistage scanning and quantified by Orbitrap mass spectrometry. The amount of [14C]PhIP recovered by acid treatment of albumin 24 h following dosing accounted for 7.2–21.3% of the [14C]PhIP bound to albumin based on accelerator mass spectrometry measurements. 2-Amino-1-methyl-6-(5-hydroxy)phenylimidazo[4,5-b]pyridine, a hydrolysis product of the Cys34 S–N linked sulfenamide adduct of PhIP, was not detected in either acid-treated or protease-treated samples. These findings suggest that a portion of the PhIP bound to albumin in vivo probably occurs as an acid-labile sulfinamide adduct formed at the Cys34 residue.
- Research Organization:
- Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Organization:
- USDOE National Nuclear Security Administration (NNSA)
- Grant/Contract Number:
- AC52-07NA27344
- OSTI ID:
- 1513115
- Report Number(s):
- LLNL-JRNL-769924; 961189
- Journal Information:
- Chemical Research in Toxicology, Vol. 30, Issue 2; ISSN 0893-228X
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
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journal | December 2019 |
Mass Spectrometry-Based Methodologies for Targeted and Untargeted Identification of Protein Covalent Adducts (Adductomics): Current Status and Challenges
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journal | April 2019 |
Biomonitoring an albumin adduct of the cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in humans
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journal | September 2018 |
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journal | May 2018 |
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