Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice

Minerva Ramos-Gomez, Patrick M. Dolan, Ken Itoh, Masayuki Yamamoto, Thomas W Kensler

Research output: Contribution to journalArticle

Abstract

The cancer chemopreventive actions of oltipraz (4-methyl-5-[2-pyrazinyl]-1,2-dithiole-3-thione) have been primarily associated with the induction of phase 2 detoxifying enzymes through transcriptional activation of the antioxidant response element (ARE) in the promoter regions of these genes. The transcription factor Nrf2 has been shown to bind to and activate AREs. Previously, we demonstrated that nrf2-deficient mice had low basal expression of phase 2 enzymes and were substantially more susceptible to benzo[a]pyrene (B[a]P)-induced neoplasia of the forestomach than wild-type. Moreover, loss of Nrf2 abrogated the chemopreventive action of oltipraz, when administered 48 h before B[a]P, an interval allowing maximal induction of many phase 2 enzymes. Oltipraz also inhibits some cytochrome P450s involved in the bioactivation of B[a]P. In the present study we observed that oltipraz had no protective effect on tumor burden in the forestomach of nrf2-deficient mice when administered 1 h before B[a]P, a timeline that selectively optimizes for possible inhibitory effects on cytochrome P450s. To evaluate the role of nrf2 genotype on B[a]P disposition, levels of B[a]P-DNA adducts were measured as tetrols released from DNA isolated from target (forestomach) and non-target tissues (liver) of wild-type and nrf2-deficient mice treated with either vehicle or oltipraz 1 or 48 h before B[a]P. Levels of B[a]P-DNA adducts in forestomach were significantly higher in nrf2-deficient compared with wild-type mice. Oltipraz treatment at 1 or 48 h before B[a]P had no protective effect on forestomach tetrol levels in nrf2-deficient mice, whereas a significant reduction was observed in wild-type mice treated with oltipraz 48 h, but not 1 h, before carcinogen. Combining all treatments and genotypes, there was a strong correlation (R2 = 0.91) between levels of B[a]P-DNA adducts in forestomach and subsequent yield of tumors. In contrast to the results in forestomach, nrf2 genotype did not modify hepatic B[a]P-DNA adduct levels while both oltipraz treatments were protective, suggesting that Nrf2-independent mechanisms (e.g. P450 inhibition) for oltipraz can also occur in vivo in some tissues.

Original languageEnglish (US)
Pages (from-to)461-467
Number of pages7
JournalCarcinogenesis
Volume24
Issue number3
DOIs
StatePublished - Mar 1 2003

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Genotype
Benzo(a)pyrene
Neoplasms
Cytochromes
Enzymes
Antioxidant Response Elements
benzo(a)pyrene-DNA adduct
oltipraz
Liver
Tumor Burden
Genetic Promoter Regions
Carcinogens
Transcriptional Activation
Transcription Factors
DNA
Genes

ASJC Scopus subject areas

  • Cancer Research

Cite this

Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice. / Ramos-Gomez, Minerva; Dolan, Patrick M.; Itoh, Ken; Yamamoto, Masayuki; Kensler, Thomas W.

In: Carcinogenesis, Vol. 24, No. 3, 01.03.2003, p. 461-467.

Research output: Contribution to journalArticle

Ramos-Gomez, Minerva ; Dolan, Patrick M. ; Itoh, Ken ; Yamamoto, Masayuki ; Kensler, Thomas W. / Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice. In: Carcinogenesis. 2003 ; Vol. 24, No. 3. pp. 461-467.
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