Covalent Modification of Proteins and Peptides by the Quinone Methide from 2-tert-Butyl-4,6-dimethylphenol: Selectivity and Reactivity with Respect to Competitive Hydration

Paul G. McCracken, Judy L. Bolton, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Covalent modification of cellular nucleophiles by electrophilic metabolites has been shown to be an important pathway in the toxicological activity of many xenobiotic compounds. The p-quinone methide (4-allylidene-2,5-cyclohexadien-1-one, QM) oxidative metabolites of the 4-alkylphenols are a chemical family whose toxicology has been well described. The reactivity of the QM from 2-tertbutyl-4,6-dimethylphenol (BDMP-QM) with respect to hydration has been studied in the 3 < pH < 11 range in order to examine selectivity for competitive reaction with biological nitrogen nucleophiles. The reactivity of BDMP-QM was examined with human hemoglobin A (HbA), angiotensin-III (AIII), amino acids, and amines. Nucleophilic selectivity (kNu/kH2O) and reactivity (kNu) in aqueous solution (7 < pH < 8) for addition of these biological nucleophiles to BDMP-QM demonstrate (i) that adduct formation is competitive with hydration at low nucleophile concentrations and (ii) that proteins, peptides, and tyrosine show enhanced reactivity toward QMs, relative to simple amino acids and related compounds. All adducts were characterized by electrospray mass spectrometry (ESMS). These results provide strong evidence supporting the toxicity of QM metabolites via facile alkylation of nucleophilic nitrogen sites in proteins and peptides, even when present in low concentration in aqueous solution under physiological conditions.

Original languageEnglish (US)
Pages (from-to)1820-1825
Number of pages6
JournalJournal of Organic Chemistry
Volume62
Issue number6
DOIs
StatePublished - 1997
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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