Possible involvement of oxidative stress in dicyclanil-induced hepatocarcinogenesis in mice.
Our previous study suggested the possibilities that dicyclanil (DC), a nongenotoxic carcinogen, produces oxidative stress in the liver of the two-stage hepatocarcinogenesis model of mice and the stress induced probably causes secondary oxidative DNA damage. However, clear evidences demonstrating the relationship between DC-induced hepatocarcinogenesis, oxidative stress, and oxidative DNA damage have not been obtained. To clarify the relationship, further investigations were performed in the liver of the partially hepatectomized (PH) mice maintained on diet containing 1,500 ppm of DC for 13 and 26 weeks after intraperitoneal injection of dimethylnitrosamine (DMN). Significant increases in mRNA expressions of some metabolism- and oxidative stress-related genes with a formation of gamma-glutamyltranspeptidase (GGT) positive foci were observed in the DMN + DC + PH group by the treatment of DC for 13 and 26 weeks. The levels of 8-hydroxy-deoxyguanosine (8-OHdG) in the liver DNA also significantly increased in mice of the DMN + DC + PH group at weeks 13 and 26 and mice given DC alone for 26 weeks. The in vitro measurement of reactive oxygen species (ROS) generation from the mouse liver microsomes showed a significant increase of ROS production in the presence of DC. These results suggest that DC induces oxidative stress which is probably derived from its metabolic pathway, partly, and support our previous speculation that oxidative stress plays one of the important roles in the DC-induced hepatocarcinogenesis in mice.
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi 183-8509, Tokyo, Japan. m-moto@cc.tuat.ac.jp
Mitsuyoshi
M
Moto
Takashi
T
Umemura
Miwa
M
Okamura
Masako
M
Muguruma
Tadashi
T
Ito
Mailan
M
Jin
Yoko
Y
Kashida
Kunitoshi
K
Mitsumori
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D045647:DNA Glycosylases / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D007605:Juvenile Hormones / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000378:metabolism; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D002273:Carcinogens; D007605:Juvenile Hormones; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000080242:8-Hydroxy-2'-Deoxyguanosine; C121718:dicyclanil; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase; C516125:Txnrd1 protein, mouse; D005723:gamma-Glutamyltransferase; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D003849:Deoxyguanosine