Coffee drinking has been associated with reduced incidence of
colorectal cancer, possibly via chemoprotection/modification of the metabolism of dietary heterocyclic
amine carcinogens such
as 2-amino-1-methyl-6-phenylimidazo-[4,5-
b]pyridine (
PhIP) by
kahweol and
cafestol palmitates (K/C), two components of unfiltered
coffee. Using the
PhIP-exposed male Fisher F344 rat as a model, K/C have been shown to reduce colonic
PhIP-
DNA adducts by > 50%. We have used the male F344 rat to investigate the effects of dietary K/C (0.02-0.2% as a 1:1 mixture) on the metabolism of
PhIP by N-
acetyltransferase- (
NAT),
sulfotransferase- (SULT), and
glutathione-dependent pathways. K/C decreased hepatic
NAT-dependent
PhIP activation by up to 80% in a dose-dependent manner. Conversely, hepatic
glutathione S-transferase (GST) activity/expression increased, e.g., 3-4 fold toward
1-chloro-2,4-dinitrobenzene (total activity), up to 23-fold toward
4-vinylpyridine (rGSTP1), and approximately 7-fold for rGSTA2
protein. These effects had fully developed after 5 days of the test diet and persisted for at least 5 days after withdrawal of K/C. Hepatic
glutathione increased two- to threefold and this increase was more short-lived than other changes. K/C did not modify hepatic SULT activity or colon
NAT and GST activities.
Benzylisothiocyanate and
black tea, which have also been shown to reduce the formation of
PhIP-
DNA adducts in this model, had little effect on hepatic
NAT, SULT, GST, or GSH. In primary culture of rat hepatocytes, both
kahweol and
cafestol palmitates reduced
NAT activity by 80%. In summary, the unique potential of K/C to convert rapid acetylators to a slow acetylator phenotype, accompanied by GST induction, might contribute to
chemoprevention against
cancers associated with heterocyclic
amines.