Possible involvement of oxidative stress in fenofibrate-induced hepatocarcinogenesis in rats.
To clarify whether oxidative stress is involved in the development of hepatocellular preneoplastic foci induced by fenofibrate (FF), a peroxisome proliferator-activated receptor alpha agonist, male F344/N rats were fed a diet containing 6,000, 3,000, or 0 ppm of FF for 13 weeks after N-diethylnitrosamine initiation. Two-third partial hepatectomy was performed 1 week after the FF treatment. Histopathologically, the number of hepatocellular altered foci significantly increased in the FF-treated groups with a concomitant increase in the number of hepatocytes positive for anti-Ki-67 antibody, but the number and area of glutathione S-transferase placental form (GST-P)-positive foci decreased in these groups, as compared to those in the controls. Microarray analysis or quantitative real-time reverse transcription-polymerase chine reaction demonstrated the significant up-regulations of Aco and Cyp4a1 (genes related to lipid metabolism); Gpx2, Yc2, Cat, Cyp2b15, and Ugt1a6 (metabolic oxidative stress-related genes); Apex1, Mgmt, Xrcc5, Nbn, and Gadd45a (DNA repair-related genes); and Ccnd1 (cell cycle-related genes) in the FF-treated groups, and the significant down-regulations of Cyp1a2, Gsta2, Gstm2, and Gstm3 (phase I or II metabolism-related genes); Mlh1 and Top1 (DNA repair-related genes); and Cdkn1a, Cdkn1b, Chek2, and Gadd45b (cell cycle/apoptosis-related genes) in these rats. FF-treatment increased the activity of enzymes such as carnitine acetyltransferase, carnitine palmitoyltransferase, fatty acyl-CoA oxidizing system, and catalase in the liver, but not superoxide dismutase in the liver. In addition, 8-OHdG level in liver DNA, lipofuscin deposition in hepatocytes, and in vitro reactive oxygen species production in microsomes significantly increased due to FF treatment. These results suggest that oxidative stress is involved in the development of FF-induced hepatocellular preneoplastic foci in rats.
Nishimura
Jihei
J
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, Japan. j_nisimr@cc.tuat.ac.jp
Dewa
Yasuaki
Y
Okamura
Toshiya
T
Muguruma
Masako
M
Jin
Meilan
M
Saegusa
Yukie
Y
Umemura
Takashi
T
Mitsumori
Kunitoshi
K
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D004052:Diethylnitrosamine / Q000633:toxicity; D004435:Eating / Q000187:drug effects; D011345:Fenofibrate / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006498:Hepatectomy; D000960:Hypolipidemic Agents / Q000633:toxicity*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000502:physiology*; D047493:PPAR alpha / Q000819:agonists; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000477:Alkylating Agents; D002273:Carcinogens; D000960:Hypolipidemic Agents; D019394:Ki-67 Antigen; D047493:PPAR alpha; D012334:RNA, Neoplasm; D017382:Reactive Oxygen Species; D004052:Diethylnitrosamine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D003849:Deoxyguanosine; D011345:Fenofibrate