Carcinogenesis Advance Access originally published online on February 17, 2008
Carcinogenesis 2008 29(4):834-839; doi:10.1093/carcin/bgn051
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Protective versus promotional effects of white tea and caffeine on PhIP-induced tumorigenesis and β-catenin expression in the rat
1 Linus Pauling Institute
2 College of Veterinary Medicine
3 Department of Statistics, Oregon State University, Corvallis, OR 97331, USA
4 Biochemistry Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
5 Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
* To whom correspondence should be addressed. Tel: +1 541 737 5086; Fax: +1 541 737 5077; Email: Rod.Dashwood{at}oregonstate.edu
A 1 year carcinogenicity bioassay was conducted in rats treated with three short cycles of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)/high-fat (HF) diet, followed by 2% white tea (wt/vol), 0.05% epigallocatechin-3-gallate (EGCG) or 0.065% caffeine as sole source of fluid intake. Thirty-two percent of the PhIP/HF controls survived to 1 year, compared with 50, 48.7 and 18.2% in groups given white tea, EGCG and caffeine, respectively. After 1 year, PhIP/HF controls had tumors in the colon, skin, small intestine, Zymbal’s gland, salivary gland and pancreas. For all sites combined, excluding the colon, tumor incidence data were as follows: PhIP/HF 69.5%, PhIP/HF + EGCG 48.7%, PhIP/HF + white tea 46.9% and PhIP/HF + caffeine 13.3%. Unexpectedly, a higher incidence of colon tumors was detected in rats post-treated with white tea (69%) and caffeine (73%) compared with the 42% incidence in PhIP/HF controls. In the colon tumors, β-catenin mutations were detected at a higher frequency after caffeine posttreatment, and there was a shift toward more tumors harboring substitutions of Gly34 with correspondingly high protein and messenger RNA expression seen for both β-catenin and c-Myc. c-Myc expression exhibited concordance with tumor promotion, and there was a concomitant increase in cell proliferation versus apoptosis in colonic crypts. A prior report described suppression of PhIP-induced colonic aberrant crypts by the same test agents, but did not incorporate a HF diet. These findings are discussed in the context of epidemiological data which do not support an adverse effect of tea and coffee on colon tumor outcome—indeed, some such studies suggest a protective role for caffeinated beverages.
Abbreviations: ACF, aberrant crypt foci; BrdU, 5-bromo-2'-deoxyuridine; Ctnnb1, β-catenin gene (rat); EGCG, epigallocatechin-3-gallate; HF, high fat; mRNA, messenger RNA; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; Tcf, T-cell factor
Received January 16, 2008; revised February 4, 2008; accepted February 8, 2008.