The threshold dose for liver tumor promoting effects of dicyclanil in ICR mice.
To determine the threshold dose of dicyclanil (DC) that induces hepatocellular tumor-promoting effects associated with reactive oxygen species (ROS) generation via their metabolic pathways, partial hepatectomized ICR male mice were fed diets containing 0, 187.5, 375 or 750 ppm DC after an intraperitoneal injection of N-diethylnitrosamine (DEN) to initiate hepatocarcinogenesis. Immunohistochemically, the proliferating cell nuclear antigen (PCNA)-positive cell ratio was significantly increased in the DEN + 750 ppm DC group compared with the DEN alone group. However, significant increases in the number of gamma-glutamyltranspeptidase (GGT)-positive cells and formation of microsomal ROS were not observed in the DEN + DC groups compared with the DEN alone group. Real-time polymerase chain reaction (RT-PCR) showed that the expression of Cyp1a1, Cyp1a2, and OGG1genes was significantly up-regulated in mice given diets containing 375 ppm DC or more, 187.5 ppm DC or more, and 750 ppm DC, respectively. These results suggest that the threshold dose of DC that induces ROS-mediated liver tumor promotion in mice is more than 750 ppm, although expression of the Cyp1a2 gene, which is related to ROS generation, was up-regulated in the liver of mice, even at a DC dose of 187.5 ppm.
Jin
Meilan
M
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo.
Dewa
Yasuaki
Y
Kawai
Masaomi
M
Nishimura
Jihei
J
Saegusa
Yukie
Y
Kemmochi
Sayaka
S
Harada
Tomoaki
T
Shibutani
Makoto
M
Mitsumori
Kunitoshi
K
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006498:Hepatectomy; D007605:Juvenile Hormones / Q000633:toxicity*; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species; D015854:Up-Regulation / Q000187:drug effects; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D002273:Carcinogens; D007605:Juvenile Hormones; D017382:Reactive Oxygen Species; D004052:Diethylnitrosamine; C121718:dicyclanil; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D005723:gamma-Glutamyltransferase; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse