Chemoprevention of 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine-induced colon carcinogenesis by 1-O-hexyl-2,3,5-trimethylhydroquinone after initiation with 1,2-dimethylhydrazine in F344 rats.
The aim of this study is to investigate the chemopreventive effects of the synthetic phenolic antioxidant 1-O-hexyl-2,3, 5-trimethylhydroquinone (HTHQ) on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colon carcinogenesis in rats after initiation with 1,2-dimethylhydrazine (DMH) in male F344 rats. Groups of 20-22, 6-week-old male F344 rats were given four subcutaneous injections of 40 mg/kg body wt of DMH during the initial 4 weeks. They were then maintained on powdered basal diet containing 0.03% PhIP alone, PhIP together with 0.5 or 0.125% HTHQ, 0.5 or 0.125% HTHQ alone or basal diet for 32 weeks. A small number (1.1 +/- 1.1/rat) of colon tumors were induced by DMH treatment alone. After initiation with DMH, the number of colon tumors was greatly increased to 8.3 +/- 5.6 by the administration of PhIP. Additional treatment with HTHQ dose-dependently decreased the multiplicity of colon adenocarcinomas to 4.9 +/- 2.8 and 2.6 +/- 1.4 with 0.125 and 0.5%, respectively. This treatment similarly reduced atypical hyperplasias of the ventral prostate. Furthermore, HTHQ significantly reduced the multiplicity of duodenal adenocarcinomas induced by DMH + PhIP or DMH alone. Immunohistochemically, HTHQ was revealed to suppress PhIP-DNA adduct formation in the epithelial cells of the colon and prostate in a separate 2 weeks experiment. The present results clearly showed that HTHQ has chemopreventive potential for PhIP-associated colon and prostate carcinogenesis. The observed inhibition may largely be due to interference with PhIP-DNA adduct formation. In addition, HTHQ has been demonstrated to inhibit duodenal carcinogenesis in the post-initiation stage.
Futakuchi
Mitsuru
M
First Department of Pathology, Nagoya City University, Medical School, 1-Kawasomi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. futakuch@med.nagoya-cu.ac.jp
Hirose
Masao
M
Imaida
Katsumi
K
Takahashi
Satoru
S
Ogawa
Kumiko
K
Asamoto
Makoto
M
Miki
Tokutaro
T
Shirai
Tomoyuki
T
D019813:1,2-Dimethylhydrazine / Q000494:pharmacology*; D000230:Adenocarcinoma / Q000139:chemically induced / Q000517:prevention & control; D000821:Animal Feed; D000818:Animals; D002273:Carcinogens; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D018736:DNA Adducts; D004379:Duodenal Neoplasms / Q000139:chemically induced / Q000517:prevention & control; D006873:Hydroquinones / Q000494:pharmacology*; D007093:Imidazoles; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D002273:Carcinogens; D018736:DNA Adducts; D006873:Hydroquinones; D007093:Imidazoles; C081906:1-O-hexyl-2,3,5-trimethylhydroquinone; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019813:1,2-Dimethylhydrazine