title: Induction of Nrf2-mediated cellular defenses and alteration of phase I activities as mechanisms of chemoprotective effects of coffee in the liver.
abstract: Coffee consumption has been associated with a significant decrease in the risk of developing chronic diseases such as Parkinson disease, diabetes type-2 and several types of cancers (e.g. colon, liver). In the present study, a coffee-dependent induction of enzymes involved in xenobiotic detoxification processes was observed in rat liver and primary hepatocytes. In addition, coffee was found to induce the mRNA and protein expression of enzymes involved in cellular antioxidant defenses. These inductions were correlated with the activation of the Nrf2 transcription factor as shown using an ARE-reporter luciferase assay. The induction of detoxifying enzymes GSTs and AKR is compatible with a protection against both genotoxicity and cytotoxicity of aflatoxin B1 (AFB1). This hypothesis was confirmed in in vitro and ex vivo test systems, where coffee reduced both AFB1-DNA and protein adducts. Interestingly, coffee was also found to inhibit cytochrome CYP1A1/2, indicating that other mechanisms different from a stimulation of detoxification may also play a significant role in the chemoprotective effects of coffee. Further investigations in either human liver cell line and primary hepatocytes indicated that the chemoprotective effects of coffee against AFB1 genotoxicity are likely to be of relevance for humans. These data strongly suggest that coffee may protect against the adverse effects of AFB1. In addition, the coffee-mediated stimulation of the Nrf2-ARE pathway resulting in increased endogenous defense mechanisms against electrophilic but also oxidative insults further support that coffee may be associated with a protection against various types of chemical stresses.
authors.affiliation: Quality and Safety Department, Nestlé Research Center, PO Box 44, Vers-chez-les-Blanc, CH-1000 Lausanne 26, Switzerland. Christophe.Cavin@rdls.nestle.com <Christophe.Cavin@rdls.nestle.com>
authors.forename: C
authors.initials: C
authors.lastname: Cavin
authors.forename: M
authors.initials: M
authors.lastname: Marin-Kuan
authors.forename: S
authors.initials: S
authors.lastname: Langouët
authors.forename: C
authors.initials: C
authors.lastname: Bezençon
authors.forename: G
authors.initials: G
authors.lastname: Guignard
authors.forename: C
authors.initials: C
authors.lastname: Verguet
authors.forename: D
authors.initials: D
authors.lastname: Piguet
authors.forename: D
authors.initials: D
authors.lastname: Holzhäuser
authors.forename: R
authors.initials: R
authors.lastname: Cornaz
authors.forename: B
authors.initials: B
authors.lastname: Schilter
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D003069:Coffee / Q000737:chemistry*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050436:Regulatory Elements, Transcriptional; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016588:Anticarcinogenic Agents; D000975:Antioxidants; D002273:Carcinogens; D003069:Coffee; D051267:NF-E2-Related Factor 2; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D008156:Luciferases; C465260:Cyp3a2 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D005982:Glutathione Transferase; D005978:Glutathione