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

Toxicol Appl Pharmacol. 2008 Feb 1;226(3):328-37. doi: 10.1016/j.taap.2007.09.018. Epub 2007 Sep 26.

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 mumol/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrolein / chemistry
  • Acrolein / pharmacology*
  • Administration, Oral
  • Animals
  • Anticarcinogenic Agents / chemistry
  • Anticarcinogenic Agents / pharmacology*
  • Coffee* / chemistry
  • Diet
  • Diterpenes / chemistry
  • Diterpenes / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Gene Silencing
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Intestine, Small / drug effects
  • Intestine, Small / enzymology
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NAD(P)H Dehydrogenase (Quinone)
  • NADPH Dehydrogenase / genetics
  • NADPH Dehydrogenase / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • RNA, Messenger / metabolism
  • Response Elements / drug effects
  • Response Elements / genetics
  • Transcriptional Activation
  • Up-Regulation / drug effects

Substances

  • Anticarcinogenic Agents
  • Coffee
  • Diterpenes
  • Isoenzymes
  • NF-E2-Related Factor 2
  • RNA, Messenger
  • kahweol
  • Acrolein
  • cafestol
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • NADPH Dehydrogenase
  • Glutathione Transferase
  • glutathione S-transferase alpha