RGD Reference Report - Concomitant apoptosis and regeneration of liver cells as a mechanism of liver-tumor promotion by beta-naphthoflavone involving TNFalpha-signaling due to oxidative cellular stress in rats. - Rat Genome Database

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Concomitant apoptosis and regeneration of liver cells as a mechanism of liver-tumor promotion by beta-naphthoflavone involving TNFalpha-signaling due to oxidative cellular stress in rats.

Authors: Kuwata, K  Shibutani, M  Hayashi, H  Shimamoto, K  Hayashi, SM  Suzuki, K  Mitsumori, K 
Citation: Kuwata K, etal., Toxicology. 2011 Apr 28;283(1):8-17. Epub 2011 Feb 2.
RGD ID: 5130894
Pubmed: PMID:21295105   (View Abstract at PubMed)
DOI: DOI:10.1016/j.tox.2011.01.020   (Journal Full-text)

beta-Naphthoflavone (BNF) is a strong inducer of cytochrome P450 1A enzymes, and exerts liver tumor-promoting activity through enhancement of oxidative stress responses in rats. This study investigated the role of the tissue environment surrounding hepatocellular preneoplastic lesions in the early tumor-promotion stage by BNF, using enzymatically modified isoquercitrin (EMIQ) as an anti-oxidative chemopreventive agent. Male F344 rats were fed a diet containing BNF (0.5%) for 6 weeks, with or without EMIQ (0.2%) in the drinking water, 2 weeks after initiation with N-diethylnitrosamine, and were subjected to two-thirds partial hepatectomy 1 week after starting BNF-promotion. BNF-treatment increased concentrations of liver thiobarbituric acid-reactive substances, single liver cells expressing glutathione S-transferase placental form or heme oxygenase (HO)-1, and concomitant apoptosis and proliferation of liver cells. Transcript upregulation of anti-oxidative enzymes (Aldh1a1 and Nqo1), cell cycle-related molecules (Cdc20 and Cdkn2b) and inflammation-related molecules including proinflammatory cytokines (Ccl2, Col1a1, Il6, Nos2 and Serpine1) was also evident. Furthermore, BNF increased HO-1-expressing Kupffer cells and liver cells expressing tumor necrosis factor receptor 1 (TNFR1) and the TNFR1-associated death domain. Most of these BNF-induced fluctuations disappeared or were suppressed by EMIQ in conjunction with suppression of tumor-promotion. Tnf transcript levels with BNF were also suppressed by EMIQ. These results suggest that BNF-induced oxidative stress causes single liver cell toxicity, allowing subsequent concomitant apoptosis and regeneration involving inflammatory responses including TNFalpha-signaling, contributing to tumor promotion. Kupffer cells may act to protect against inflammatory stimuli induced as a result of oxidative cellular stress by BNF, causing proinflammatory cytokine level fluctuations.




  
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Original Reference(s)
COL1A1Humanliver benign neoplasm onsetISOCol1a1 (Rattus norvegicus)mRNA:increased expression:liver (rat)RGD 
Col1a1Ratliver benign neoplasm onsetIEP mRNA:increased expression:liver (rat)RGD 
Col1a1Mouseliver benign neoplasm onsetISOCol1a1 (Rattus norvegicus)mRNA:increased expression:liver (rat)RGD 


Genes (Rattus norvegicus)
Col1a1  (collagen type I alpha 1 chain)

Genes (Mus musculus)
Col1a1  (collagen, type I, alpha 1)

Genes (Homo sapiens)
COL1A1  (collagen type I alpha 1 chain)

Gene Tnfrsf1a TNF receptor superfamily member 1A Rattus norvegicus