Induction of cancer chemopreventive enzymes by coffee is mediated by transcription factor Nrf2. Evidence that the coffee-specific diterpenes cafestol and kahweol confer protection against acrolein

Larry G. Higgins, Christophe Cavin, Ken Itoh, Masayuki Yamamoto, John D. Hayes

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Mice fed diets containing 3% or 6% coffee for 5 days had increased levels of mRNA for NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase class Alpha 1 (GSTA1) of between 4- and 20-fold in the liver and small intestine. Mice fed 6% coffee also had increased amounts of mRNA for UDP-glucuronosyl transferase 1A6 (UGT1A6) and the glutamate cysteine ligase catalytic (GCLC) subunit of between 3- and 10-fold in the small intestine. Up-regulation of these mRNAs was significantly greater in mice possessing Nrf2 (NF-E2 p45 subunit-related factor 2) than those lacking the transcription factor. Basal levels of mRNAs for NQO1, GSTA1, UGT1A6 and GCLC were lower in tissues from nrf2-/- mice than from nrf2+/+ mice, but modest induction occurred in the mutant animals. Treatment of mouse embryonic fibroblasts (MEFs) from nrf2+/+ mice with either coffee or the coffee-specific diterpenes cafestol and kahweol (C + K) increased NQO1 mRNA up to 9-fold. MEFs from nrf2-/- mice expressed less NQO1 mRNA than did wild-type MEFs, but NQO1 was induced modestly by coffee or C + K in the mutant fibroblasts. Transfection of MEFs with nqo1-luciferase reporter constructs showed that induction by C + K was mediated primarily by Nrf2 and required the presence of an antioxidant response element in the 5′-upstream region of the gene. Luciferase reporter activity did not increase following treatment of MEFs with 100 μmol/l furan, suggesting that this ring structure within C + K is insufficient for gene induction. Priming of nrf2+/+ MEFs, but not nrf2-/- MEFs, with C + K conferred 2-fold resistance towards acrolein.

Original languageEnglish
Pages (from-to)328-337
Number of pages10
JournalToxicology and Applied Pharmacology
Volume226
Issue number3
DOIs
Publication statusPublished - 2008 Feb 1
Externally publishedYes

Keywords

  • Antioxidant response element
  • Arylhydrocarbon receptor
  • Glutathione S-transferase
  • NAD(P)H:quinone oxidoreductase 1
  • Nrf2

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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