Formation of DNA adducts by microsomal and peroxidase activation of p-cresol: Role of quinone methide in DNA adduct formation

Nilesh W. Gaikwad, William J. Bodell

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

We have investigated the activation of p-cresol to form DNA adducts using horseradish peroxidase, rat liver microsomes and MnO2. In vitro activation of p-cresol with horseradish peroxidase produced six DNA adducts with a relative adduct level of 8.03 ± 0.43 × 10-7. The formation of DNA adducts by oxidation of p-cresol with horseradish peroxidase was inhibited 65 and 95% by the addition of either 250 or 500 μM ascorbic acid to the incubation. Activation of p-cresol with phenobarbital-induced rat liver microsomes with NADPH as the cofactor; resulted in the formation of a single DNA adduct with a relative adduct level of 0.28 ± 0.08 × 10-7. Similar incubations of p-cresol with microsomes and cumene hydroperoxide yielded three DNA adducts with a relative adduct level of 0.35 ± 0.03 × 10-7. p-Cresol was oxidized with MnO2 to a quinone methide. Reaction of p-cresol (QM) with DNA produced five major adducts and a relative adduct level of 20.38 ± 1.16 × 10-7. DNA adducts 1,2 and 3 formed by activation of p-cresol with either horseradish peroxidase or microsomes, are the same as that produced by p-cresol (QM). This observation suggests that p-cresol is activated to a quinone methide intermediate by these activation systems. Incubation of deoxyguanosine-3′-phosphate with p-cresol (QM) resulted in a adduct pattern similar to that observed with DNA; suggesting that guanine is the principal site for modification. Taken together these results demonstrate that oxidation of p-cresol to the quinone methide intermediate results in the formation of DNA adducts. We propose that the DNA adducts formed by p-cresol may be used as molecular biomarkers of occupational exposure to toluene.

Original languageEnglish (US)
Pages (from-to)217-229
Number of pages13
JournalChemico-Biological Interactions
Volume138
Issue number3
DOIs
StatePublished - Dec 21 2001

Fingerprint

DNA Adducts
Peroxidase
Chemical activation
Horseradish Peroxidase
Liver Microsomes
Microsomes
Liver
4-cresol
quinone methide
Deoxyguanine Nucleotides
Rats
Oxidation
DNA
Guanine
Toluene
Biomarkers
Occupational Exposure
Phenobarbital
NADP
Ascorbic Acid

Keywords

  • DNA adducts
  • Microsomal activation
  • p-cresol
  • Peroxidase activation
  • Quinone methide
  • Toluene

ASJC Scopus subject areas

  • Toxicology

Cite this

Formation of DNA adducts by microsomal and peroxidase activation of p-cresol : Role of quinone methide in DNA adduct formation. / Gaikwad, Nilesh W.; Bodell, William J.

In: Chemico-Biological Interactions, Vol. 138, No. 3, 21.12.2001, p. 217-229.

Research output: Contribution to journalArticle

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