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We hypothesized that superoxide from Kupffer cells (KC) contributes to hepatocarcinogenesis.p47phox  −/−mice, deficient in phagocyte NADPH oxidase and superoxide generation, received a single dose of the hepatocarcinogen diethylnitrosamine (DEN). The following hepatic effects were observed at time points between 30 min and 35 days. Liver damage after DEN was manifested by loss of body and liver mass and of liver DNA and by an increase in apoptosis, necrosis and signs of inflammation. These effects were massive in wild-type (wt) male mice, but only very mild inp47phox  −/−mice. Regenerative DNA synthesis subsequent to liver damage was high inwtmale mice, but weak inp47phox  −/−mice. In females the apparent protection byp47phox  −/−was less pronounced than in males. Therefore, further experiments were performed with males. In KC isolated fromwtmice superoxide production was enhanced by DEN pretreatmentin vivo. Also,in vitroaddition of DEN to KC cultures induced superoxide release, similarly to lipopolysaccharide, a standard KC activator. Thus, DEN directly activateswtKC to produce superoxide. KC fromp47phox  −/−mice did not release superoxide. TNFα production by isolated KC was transiently depressed 0.5 h after DEN treatmentin vivo, but recovered rapidly. In blood serum TNFα levels ofwtmice were elevated for the initial 6 h. TNFα in KC cultures and in serum ofp47phox  −/−mice was reduced. DENin vivoinduced DNA damage (‘comets’) in hepatocytes. This damage was extensive inwtmice but much lessin p47phox  −/−mice. These studies suggest two conclusions: (i) superoxide generation by phagocytes during liver damage and inflammation aggravates genotoxic and cytotoxic effects in hepatocytes and may thus contribute to tumor initiation and promotion; (ii) DEN has a direct stimulatory effect on KC to release superoxide and TNFα.

Superoxide generation from Kupffer cells contributes to hepatocarcinogenesis: studies on NADPH oxidase knockout mice