title: Concomitant apoptosis and regeneration of liver cells as a mechanism of liver-tumor promotion by β-naphthoflavone involving TNFα-signaling due to oxidative cellular stress in rats.
abstract: β-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 TNFα-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.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kuwata
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Shim-Mo
authors.initials: SM
authors.lastname: Hayashi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019324:beta-Naphthoflavone / Q000494:pharmacology*
chemical_list: D002273:Carcinogens; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha; C016527:isoquercitrin; D019324:beta-Naphthoflavone; D011794:Quercetin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D005982:Glutathione Transferase