Nitrofurazone-induced gene expressions in rat hepatocytes and their modification by N-acetylcysteine.
The antibiotic nitrofurazone (NF) at a subtoxic dose has been shown to increase hepatocyte DNA synthesis with no preceding cell damage or necrosis. This was suppressed by concomitant administration of the antioxidant N-acetylcysteine (NAC), which suggests that free radical production is involved in the process. In this study, male F344 rats were given a single oral subtoxic dose of NF to investigate the changes in genes implicated in hepatocyte proliferation between 1 and 20h postdose by real-time PCR. Some rats were also given NAC to examine the involvement of free radicals. There were transient and sequential increases in mRNA levels of c-myc and c-jun shortly after the administration, followed by tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-alpha (TGF-alpha), c-Ha-ras, and cyclin E. The increases were blocked by concomitant administration of NAC. In contrast, there were no NF-specific increases in c-fos, hepatocyte growth factor, epidermal growth factor or cyclin D1 mRNAs. These results indicate that the induction of hepatocyte proliferation by NF is triggered by free radicals, with a pathway involving increases in c-jun, c-myc, TNF-alpha, TGF-alpha, c-Ha-ras, and cyclin E. The results also indicate that NF-induced proliferation resembles that of other mitogens.
Ito
Kyoko
K
Safety Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., 1-8 Azusawa 1-Chome, Itabashi-ku, Tokyo 174-8511, Japan. itou@yamanouchi.co.jp
Kajikawa
Satoru
S
Nii
Aisuke
A
Doi
Kunio
K
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D004347:Drug Interactions; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006133:Growth Substances / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009583:Nitrofurazone / Q000633:toxicity*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000891:Anti-Infective Agents, Local; D015415:Biomarkers; D017931:DNA Primers; D005609:Free Radicals; D006133:Growth Substances; D015513:Oncogene Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000111:Acetylcysteine; D009583:Nitrofurazone