Effect of phenobarbital on hepatic cell proliferation and apoptosis in mice deficient in the p50 subunit of NF-kappaB.
Phenobarbital (PB) is a nongenotoxic tumor promoter in the liver. One mechanism by which PB may exert its tumor promoting activity is by inducing oxidative stress. We previously found that PB administration increased hepatic NF-kappaB DNA binding activity. In this study we examined the hypothesis that the effects of PB on cell proliferation and apoptosis are dependent on NF-kappaB. We used a mouse model that is deficient in the p50 subunit of NF-kappaB; previous studies had found that p50-/- mice were less sensitive to the induction of hepatic cell proliferation by PCBs or peroxisome proliferators. Mice (p50-/- and wild-type B6129) were fed a control diet or one containing 0.05% PB for 3, 10 or 34 days. At the end of the experiment, the mice were euthanized and livers removed and processed. PB increased cell proliferation at 3 and 10 days (but not at 34 days), but the deletion of the NF-kappaB p50 subunit did not inhibit these increases. p50-/- Mice had higher cell proliferation at the 3 day (only in mice fed PB) and 34-day timepoints. PB decreased hepatocyte apoptosis after 3 days, slightly decreased it after 10 days, and did not affect it after 34 days. The deletion of the NF-kappaB p50 subunit did not influence PB's effect on apoptosis. In p50-/- mice, apoptosis was increased after 3 or 10 days compared to wild-type mice, but no effect was seen after 34 days. The hepatic expression of the NF-kappaB-regulated gene TNF-alpha correlated more with the hepatic cell proliferation data than with hepatic apoptosis, and was not decreased by the deletion of the p50 subunit. These findings show that the p50 subunit of NF-kappaB is not required for the alteration of hepatocyte proliferation or apoptosis by PB up to 34 days after its administration.
Tharappel
Job C
JC
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40506-0054, USA.
Spear
Brett T
BT
Glauert
Howard P
HP
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects*; D004032:Diet; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020868:Gene Silencing; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000172:deficiency* / Q000235:genetics; D010634:Phenobarbital / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D002273:Carcinogens; D052002:NF-kappa B p50 Subunit; D014409:Tumor Necrosis Factor-alpha; D010634:Phenobarbital