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)

Food Chem Toxicol. 2005 Mar;43(3):433-41. doi: 10.1016/j.fct.2004.11.009.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Cell Line, Tumor
  • Coffee / chemistry*
  • Cytochrome P-450 Enzyme System / metabolism
  • Dimethylnitrosamine
  • Diterpenes / pharmacology*
  • Dose-Response Relationship, Drug
  • Glutathione Transferase / metabolism
  • Humans
  • Imidazoles / toxicity*
  • Liver / cytology
  • Liver / drug effects*
  • Liver / enzymology
  • Micronucleus Tests
  • Mutagens / toxicity*
  • Nitrosamines / toxicity*
  • Sulfotransferases / metabolism

Substances

  • Coffee
  • Diterpenes
  • Imidazoles
  • Mutagens
  • Nitrosamines
  • kahweol
  • cafestol palmitate
  • Cytochrome P-450 Enzyme System
  • 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
  • cafestol
  • Glutathione Transferase
  • Sulfotransferases
  • Dimethylnitrosamine