title: Coffee diterpenes prevent the genotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N-nitrosodimethylamine in a human derived liver cell line (HepG2).
abstract: Aim of the present experiments was to study the genotoxic effects of coffee diterpenoids, namely cafestol palmitate and a mix of cafestol and kahweol (C+K) in human derived hepatoma (HepG2) cells. Furthermore, we investigated the potential protective properties of these substances towards carcinogens contained in the human diet, namely N-nitrosodimethylamine (NDMA) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). C+K and cafestol palmitate were tested over a broad dose range in micronucleus (MN) assays and no indication for genotoxic effects was seen. In combination experiments with PhIP (300 microM), pronounced inhibition (approximately 1.7-fold) of MN formation was observed with C+K and cafestol palmitate at dose levels > or = 0.9 and 1.7 microg/ml, respectively. Enzyme measurements indicate that the protection is due to inhibition of sulfotransferase, an enzyme involved in the activation of the amine, and/or to induction of UDP-glucuronosyltransferase which detoxifies the DNA-reactive metabolites of PhIP. Furthermore, a significant increase of glutathione-S-transferase was seen, whereas the activities of cytochrome P-450 1A1 and N-acetyltransferase 1 were not significantly altered. Also in combination experiments with C+K and NDMA, strong protective effects (50% reduction of genotoxicity) were seen at low dose levels (> or = 0.3 microg/ml). Since inhibition of MN was also observed when C+K were added after incubation with NDMA, it is likely that the chemoprotective effects are due to induction of DNA repair enzymes. Comparison of data on the effects of C+K on the cholesterol metabolism, which was investigated in earlier in vivo studies, with the present findings suggests that DNA-protective effects take place at exposure levels which are substantially lower than those which cause hypercholesterolemia.
authors.affiliation: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: B J
authors.initials: BJ
authors.lastname: Majer
authors.forename: E
authors.initials: E
authors.lastname: Hofer
authors.forename: C
authors.initials: C
authors.lastname: Cavin
authors.forename: E
authors.initials: E
authors.lastname: Lhoste
authors.forename: M
authors.initials: M
authors.lastname: Uhl
authors.forename: H R
authors.initials: HR
authors.lastname: Glatt
authors.forename: W
authors.initials: W
authors.lastname: Meinl
authors.forename: S
authors.initials: S
authors.lastname: Knasmüller
mesh_terms: D000704:Analysis of Variance; D045744:Cell Line, Tumor; D003069:Coffee / Q000737:chemistry*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004128:Dimethylnitrosamine; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D009602:Nitrosamines / Q000633:toxicity*; D015238:Sulfotransferases / Q000378:metabolism
chemical_list: D003069:Coffee; D004224:Diterpenes; D007093:Imidazoles; D009153:Mutagens; D009602:Nitrosamines; C053401:kahweol; C033998:cafestol palmitate; D003577:Cytochrome P-450 Enzyme System; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C053400:cafestol; D005982:Glutathione Transferase; D015238:Sulfotransferases; D004128:Dimethylnitrosamine