Inhibitory effect of natural coumarin compounds, esculetin and esculin, on oxidative DNA damage and formation of aberrant crypt foci and tumors induced by 1,2-dimethylhydrazine in rat colons.
The effects of esculetin (6,7-dihydroxycoumarin) and its 6-glycoside, esculin, on 8-oxo-2'-deoxyguanosine (8-oxodG) formation and carcinogenesis induced by a chemical carcinogen, 1,2-dimethylhydrazine (DMH), were examined in the colons of male Fischer 344 rats. Animals were given water containing esculetin or esculin for 7 d before subcutaneous injection of DMH (20 mg/kg body wt), killed 24 h after DMH treatment, and the levels of thiobarbituric acid reactive substances (TBARS) and 8-oxodG in the colons were determined. Both esculetin and esculin suppressed significantly the DMH-induced increases in 8-oxodG and TBARS in rat colon mucosa. We further investigated the modifying effect of esculin intake on the development of DMH-induced colonic aberrant crypt foci (ACF). Animals were given DMH once a week for 4 weeks to induce ACF. They then received water containing esculin ad libitum for 5 weeks (initiation phase) or 11 weeks after DMH treatment (post-initiation phase). Animals in the positive control group received tap water throughout the experiment. At the end of the experiment (16 weeks), the ingestion of esculin during the initiation phase significantly reduced the incidence of gross tumors, the number of ACF per rat and the mean number of AC per focus, while the esculin treatment during the post-initiation phase significantly decreased only the number of ACF per rat. These results suggest that esculin intake has an inhibitory effect on DMH-induced oxidative DNA damage and carcinogenesis in rat colons.
Kaneko
Takao
T
Redox Regulation Research Group, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo, Japan. kanekot@tmig.or.jp
Tahara
Shoichi
S
Takabayashi
Fumiyo
F
D019813:1,2-Dimethylhydrazine / Q000633:toxicity; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D004929:Esculin / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014468:Umbelliferones / Q000494:pharmacology*
D000975:Antioxidants; D002273:Carcinogens; D017392:Thiobarbituric Acid Reactive Substances; D014468:Umbelliferones; D004929:Esculin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D019813:1,2-Dimethylhydrazine; C007628:esculetin