title: Superoxide deficiency attenuates promotion of hepatocarcinogenesis by cytotoxicity in NADPH oxidase knockout mice.
abstract: Long-term exposure to carcinogens combined with chronic hepatitis contributes greatly to the worldwide high incidence of hepatocellular carcinoma (HCC). It is still unclear to which extent the release of pro-inflammatory reactive oxygen or nitrogen species contributes to the development of this malignancy. Here, we aim to elucidate the role of superoxide in a model of chemical hepatocarcinogenesis. p47(phox) knockout mice (KO), lacking superoxide formation by phagocytic NADPH oxidase (phox), and wild-type animals (WT) were subjected to two different initiation-promotion protocols: (1) single dose of diethylnitrosamine (DEN) at 6 weeks of age followed by phenobarbital (PB) via diet, or ethanol (EtOH) in drinking water; (2) DEN at neonatal age followed by three cytotoxic doses of DEN at intervals of 6-7 weeks. The appearance of tumors and prestages was quantified. There was no obvious difference in the capacity of DEN to initiate hepatocarcinogenesis in KO and WT mice. PB promoted tumor development in both genotypes without significant difference. EtOH induced steatosis significantly less in KO than in WT liver, but had no effect on tumor formation in either genotype. However, hepatocarcinogenesis by three cytotoxic DEN doses after neonatal initiation was attenuated significantly in KO. Macrophages/monocytes identified by the specific antigen F4/80 were more abundant in KO than in WT liver, possibly reflecting a compensatory response. We conclude that phox-derived superoxide is not essential but is supportive for the promotion of hepatocarcinogenesis by cytotoxic doses of DEN. The production of superoxide may therefore contribute to the promotion of hepatocarcinogenesis by cytotoxic/pro-inflammatory stimuli.
authors.affiliation: Department of Medicine I, Comprehensive Cancer Center, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Wien, Austria.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Parzefall
authors.forename: Constanze
authors.initials: C
authors.lastname: Freiler
authors.forename: Olga
authors.initials: O
authors.lastname: Lorenz
authors.forename: Helga
authors.initials: H
authors.lastname: Koudelka
authors.forename: Teresa
authors.initials: T
authors.lastname: Riegler
authors.forename: Marzieh
authors.initials: M
authors.lastname: Nejabat
authors.forename: Eveline
authors.initials: E
authors.lastname: Kainzbauer
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
authors.forename: Rolf
authors.initials: R
authors.lastname: Schulte-Hermann
mesh_terms: D000818:Animals; D003043:Cocarcinogenesis; D004052:Diethylnitrosamine / Q000633:toxicity; D000431:Ethanol / Q000633:toxicity; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D013481:Superoxides; D004052:Diethylnitrosamine; D000431:Ethanol; D019255:NADPH Oxidases; D010634:Phenobarbital