Suppressive effect of Siraitia grosvenorii extract on dicyclanil-promoted hepatocellular proliferative lesions in male mice.
Dicyclanil (DC) generates reactive oxygen species (ROS) due to Cyp1a1 induction, and DNA damage caused by oxidative stress is probably involved in hepatocarcinogenesis in mice. To clarify the modifying effect of the Siraitia grosvenorii extract (SGE), which has antioxidative properties, we employed a 2-stage liver carcinogenesis model in partially hepatectomized male ICR mice. Mice maintained on diet containing DC at a concentration of 1,500 ppm for 9 weeks after a single intraperitoneal injection of diethylnitrosamine (DEN) at a dose of 30 mg/kg and they were given water containing 2,500 ppm of SGE for 11 weeks including 2 weeks as pre-administration on DC. SGE inhibited the induction of gamma-glutamyltranspeptidase-positive hepatocytes, lipid peroxidation, and gene expression of Cyp1a1, all of which were caused by DC. To examine whether SGE indirectly inhibits Cyp1a1 expression induced by inhibition of aryl hydrocarbon receptor (Ahr)-mediated signal transduction caused by DC, mice with high (C57BL/6J mice) and low affinities (DBA/2J mice) to Ahr were given DC-containing diet and/or SGE-containing tap water for 2 weeks. Cyp1a1 gene expression was significantly lower in C57BL/6J mice administered DC + SGE than in C57BL/6J mice administered DC alone; there was no difference in the Cyp1a1 expression between DBA/2J mice administered DC + SGE and DC alone. These results suggest that SGE suppresses the induction of Cyp1a1, leading to inhibition of ROS generation and consequently inhibited hepatocarcinogenesis, probably due to suppression of Ahr activity.
Matsumoto
Sayaka
S
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Jin
Meilan
M
Dewa
Yasuaki
Y
Nishimura
Jihei
J
Moto
Mitsuyoshi
M
Murata
Yuji
Y
Shibutani
Makoto
M
Mitsumori
Kunitoshi
K
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D019662:Cucurbitaceae / Q000737:chemistry*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007605:Juvenile Hormones / Q000737:chemistry / Q000633:toxicity; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000187:drug effects / Q000378:metabolism
D000477:Alkylating Agents; D000975:Antioxidants; D002273:Carcinogens; D007605:Juvenile Hormones; D010936:Plant Extracts; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D017392:Thiobarbituric Acid Reactive Substances; D004052:Diethylnitrosamine; C121718:dicyclanil; D019363:Cytochrome P-450 CYP1A1; D005723:gamma-Glutamyltransferase