title: 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.
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.
authors.affiliation: Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK. l.y.higgins@dundee.ac.uk
authors.forename: Larry G
authors.initials: LG
authors.lastname: Higgins
authors.forename: Christophe
authors.initials: C
authors.lastname: Cavin
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: John D
authors.initials: JD
authors.lastname: Hayes
mesh_terms: D000171:Acrolein / Q000737:chemistry / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D003069:Coffee / Q000737:chemistry; D004032:Diet; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D020868:Gene Silencing; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D003069:Coffee; D004224:Diterpenes; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; C053401:kahweol; D000171:Acrolein; C053400:cafestol; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha