Gene expression analysis in mice liver on hepatocarcinogenesis by flumequine.
mRNA expression profiles in the liver from mice treated with flumequine (FL) were analyzed in order to elucidate the mechanism of its tumor-promoting effect. The liver from a C3H/He mouse that received a diet containing 4,000 ppm of FL for 4 weeks was examined by cDNA microarray in comparison with an untreated mouse. Furthermore, to obtain a more comprehensive sequence, time-course changes in selected genes were determined by real-time RT-PCR. Microarray analysis revealed 15 upregulated and 9 downregulated genes in an FL-treated mouse. The upregulated genes included signal transducers and cell cycle regulators. In addition, the levels of stress response genes, particularly glutathione S-transferase (GST) alpha and GSTmu, were very high, indicating the generation of oxidative stress. On the other hand, the downregulated genes included phase I metabolic enzymes, such as cytochrome P450 (CYPs) enzymes, and apoptosis-associated proteins. These changes were confirmed by quantitative RT-PCR and were generally consistent with each other. Time-course observations revealed consistent results, particularly with regard to GSTalpha, GSTmu, ERK5, and CYP2E1. In addition, the expression of 8-oxoguanine DNA glycosylase 1 (OGG1) was increased in a time-dependent manner. These results suggest the possibility that responses against oxidative stress may play a major role in hepatocarcinogenesis by FL in mice.
Kashida
Yoko
Y
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 183-8509 Fuchu, Tokyo, Japan. kashida.1@osu.edu
Takahashi
Akiko
A
Moto
Mitsuyoshi
M
Okamura
Miwa
M
Muguruma
Masako
M
Jin
Meilan
M
Arai
Katsuhiko
K
Mitsumori
Kunitoshi
K
D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D024841:Fluoroquinolones / Q000633:toxicity*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000890:Anti-Infective Agents; D002273:Carcinogens; D004798:Enzymes; D024841:Fluoroquinolones; D012333:RNA, Messenger; C012976:flumequine