Protective effects of coffee diterpenes against aflatoxin B1-induced genotoxicity: mechanisms in rat and human cells.
The coffee-specific diterpenes cafestol and kahweol (C + K) have been reported to be anticarcinogenic in several animal models. Proposed mechanisms involve a co-ordinated modulation of several enzymes responsible for carcinogen detoxification, thus preventing reactive agents interacting with critical target sites. To address the human relevance of the chemoprotective effects of C + K against aflatoxin B(1) (AFB1) genotoxicity observed in rat liver, and to compare the mechanisms of protection involved in both species, animal and human hepatic in vitro test systems were applied. In rat primary hepatocytes, C + K reduced the expression of cytochrome P450 CYP 2C11 and CYP 3A2, the key enzymes responsible for AFB1 activation to the genotoxic metabolite aflatoxin B1-8,9 epoxide (AFBO). In addition, these diterpenes induced significantly GST Yc2, the most efficient rat GST subunit involved in AFBO detoxification. These effects of C + K resulted in a marked dose-dependent inhibition of AFB1-DNA binding in this rat in vitro culture system. Their relevance in humans was addressed using liver epithelial cell lines (THLE) stably transfected to express AFB1 metabolising cytochrome P450s. In these cells, C + K also produced a significant inhibition of AFB1-DNA adducts formation linked with an induction of the human glutathione S-transferase GST-mu. Altogether, these results suggest that C + K may have chemoprotective activity against AFB1 genotoxicity in both rats and humans.
Cavin
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Nestlé Research Center, PO Box 44, Vers-chez-les Blanc, CH-1000 26, Lausanne, Switzerland. christophe.cavin.@rdls.nestle.com
Mace
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Offord
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EA
Schilter
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B
D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D018890:Chemoprevention; D003069:Coffee / Q000737:chemistry*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018736:DNA Adducts / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
D003069:Coffee; D018736:DNA Adducts; D004224:Diterpenes; C053401:kahweol; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; C053400:cafestol