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.
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 N(2)-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 N(2)-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.
Turesky
Robert J
RJ
Division of Chemistry, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, USA. rturesky@nctr.fda.gov
Richoz
Janique
J
Constable
Anne
A
Curtis
Kellie D
KD
Dingley
Karen H
KH
Turteltaub
Kenneth W
KW
D000818:Animals; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D003069:Coffee / Q000502:physiology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D018736:DNA Adducts / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004798:Enzymes / Q000096:biosynthesis*; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D005982:Glutathione Transferase / Q000096:biosynthesis; D007093:Imidazoles / Q000378:metabolism* / Q000633:toxicity; D007527:Isoenzymes / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009152:Mutagenicity Tests; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D002273:Carcinogens; D003069:Coffee; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D018736:DNA Adducts; D004798:Enzymes; D007093:Imidazoles; D007527:Isoenzymes; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019388:Cytochrome P-450 CYP1A2; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha