Potential chemoprotective effects of the coffee components kahweol and cafestol palmitates via modification of hepatic N-acetyltransferase and glutathione S-transferase activities.
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.
Division of Molecular Epidemiology, National Center for Toxicological Research, Jefferson, Arkansas, USA. wolfgang.huber@meduniwien.ac.at
Wolfgang W
WW
Huber
Candee H
CH
Teitel
Brian F
BF
Coles
Roberta S
RS
King
Frederick W
FW
Wiese
Keith R
KR
Kaderlik
Daniel A
DA
Casciano
Joseph G
JG
Shaddock
Gerard J
GJ
Mulder
Kenneth F
KF
Ilett
Fred F
FF
Kadlubar
D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D003069:Coffee / Q000737:chemistry; D003106:Colon / Q000187:drug effects / Q000201:enzymology; D018736:DNA Adducts / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism*; D017879:Isothiocyanates / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D013662:Tea / Q000737:chemistry; D013997:Time Factors
D002273:Carcinogens; D003069:Coffee; D018736:DNA Adducts; D004224:Diterpenes; D007093:Imidazoles; D017879:Isothiocyanates; D013662:Tea; C053401:kahweol; C033998:cafestol palmitate; C031403:benzyl isothiocyanate; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D000123:Acetyltransferases; D005982:Glutathione Transferase