The effects of coffee on enzymes involved in metabolism of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in rats

Robert J. Turesky, Janique Richoz, Anne Constable, Kellie D. Curtis, Karen H. Dingley, Ken W Turteltaub

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

The effects of coffee on the metabolism and genotoxicity of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were investigated. Coffee diminished the bacterial mutagenicity of PhIP in the Ames reversion assay through inhibition of cytochrome P450 1A2 (CYP1A2), a key enzyme involved in the metabolic activation of PhIP. When given as part of the diet (0, 1 or 5% w/w) to male Fischer-344 rats for 2 weeks, coffee affected the expression of hepatic enzymes involved in PhIP metabolism. Coffee increased the expression of CYP1A2 by 16-fold in the 5% coffee-treated group, and approximately half of this inductive effect was attributed to caffeine. Coffee also increased the expression of enzymes involved in the detoxication of PhIP. A 2-fold increase in expression of glutathione S-transferase alpha was observed, UDP-glucuronosyl transferase (UGTs) activities of p-nitrophenol increased 2-fold, while N2-and N3-glucuronidation of the genotoxic metabolite 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP) increased by 1.3-fold in the 5% coffee-treated over the control group. The amount of PhIP (0.75 mg/kg, 24 h) eliminated in urine as the N2-and N3-glucuronide conjugates of HONH-PhIP increased by 1.8- and 2.5-fold, respectively, in the 5% coffee-treated group over control rats, suggesting either increased rates of N-oxidation of PhIP or N-glucuronidation of HONH-PhIP. Despite the strong induction of CYP1A2, there was no increase in PhIP-DNA adduct formation in colon and pancreas while liver adducts decreased by 50% over control animals. These data suggest that the effect of coffee on inhibition of PhIP N-oxidation and ensuing DNA damage is more important in vivo than its effect on induction of PhIP N-hydroxylation.

Original languageEnglish (US)
Pages (from-to)251-265
Number of pages15
JournalChemico-Biological Interactions
Volume145
Issue number3
DOIs
StatePublished - Jun 15 2003
Externally publishedYes

Keywords

  • Caffeine
  • Chemoprotection
  • Coffee
  • Heterocyclic aromatic amines
  • Metabolism

ASJC Scopus subject areas

  • Toxicology

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