Immunohistochemical analyses at the late stage of tumor promotion by oxfendazole in a rat hepatocarcinogenesis model.
The present study was performed to characterize immunohistochemically the expression levels of molecules related to not only xenobiotic and antioxidant functions but also cell proliferation and apoptosis in neoplastic lesions induced by the benzimidazole anthelmintic, oxfendazole (OX), at the late stage of its tumor promotion in a rat hepatocarcinogenesis model. Male F344 rats were initiated with an intraperitoneal injection of 200 mg/kg N-diethylnitrosamine, and 2 weeks later they were fed a diet containing 0% (basal diet) or 0.05% OX for 26 weeks. All animals were subjected to a two-thirds partial hepatectomy at week 3 and killed at week 28. Histopathologically, OX increased the incidence and multiplicity of altered foci (4.0- and 3.6-fold, respectively) and hepatocellular adenomas (HCAs) (3.0- and 5.5-fold, respectively). OX treatment induced 5.2- and 5.6-fold increases in the number of proliferating cell nuclear antigen (PCNA)-positive cells and single-stranded DNA (ssDNA)-positive cells in HCAs compared with the surrounding tissue, respectively. Staining for the cell cycle regulators P21 and C/EBPα and the AhR-regulated CYP1A1 molecules decreased but increased reactivity of the Nrf2-regulated, detoxifing/antioxidant molecules aldo-keto reductase 7 (AKR7) and glutathione peroxidase 2 (GPX2) were also seen in HCAs compared with the surrounding hepatocytes. These results suggest that dysregulation of cell proliferation and apoptosis and escape from oxidative stress elicited by OX treatment play an important role in OX-induced hepatocarcinogenesis in rats.
Dewa
Yasuaki
Y
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Nishimura
Jihei
J
Jin
Meilan
M
Kawai
Masaomi
M
Saegusa
Yukie
Y
Kenmochi
Sayaka
S
Shimamoto
Keisuke
K
Harada
Tomoaki
T
Shibutani
Makoto
M
Mitsumori
Kunitoshi
K
D018248:Adenoma, Liver Cell / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000871:Anthelmintics / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003043:Cocarcinogenesis; D004277:DNA, Single-Stranded / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D000871:Anthelmintics; D001562:Benzimidazoles; D002273:Carcinogens; D018797:Cell Cycle Proteins; D004277:DNA, Single-Stranded; D018809:Proliferating Cell Nuclear Antigen; D004052:Diethylnitrosamine; C011030:oxfendazole