title: WY-14,643 induced cell proliferation and oxidative stress in mouse liver are independent of NADPH oxidase.
abstract: Long-term exposure of rodents to peroxisome proliferators leads to increases in peroxisomes, hepatocellular proliferation, oxidative damage, suppressed apoptosis, and ultimately results in the development of hepatic adenomas and carcinomas. Peroxisome proliferators-activated receptor (PPAR)alpha was shown to be required for these pleiotropic responses; however, Kupffer cells, resident liver macrophages, were also identified as playing a role in peroxisome proliferators-induced effects, independently of PPARalpha. Previous studies showed that oxidants from NADPH (nicotinamide adenine dinucleotide phosphate, reduced) oxidase mediate acute effects of peroxisome proliferators in rodent liver. To determine if Kupffer cell oxidants are also involved in chronic effects, NADPH oxidase-deficient (p47(phox)-null) mice were fed 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (WY-14,643)-containing diet (0.1% wt/wt) for 1 week, 5 weeks, or 5 months along with Pparalpha-null and wild type mice. As expected, no change in liver size, cell replication rates, or other phenotypic effects of peroxisome proliferators were observed in Pparalpha-null mice. Through 5 months of treatment, the p47(phox)-null and wild type mice exhibited peroxisome proliferators-induced adverse liver effects, along with increased oxidative DNA damage and increased cell proliferation, a response that is potentially mediated through nuclear factor kappa B (NFkB). Suppressed apoptosis caused by WY-14,643 was dependent on both NADPH oxidase and PPARalpha. Collectively, these findings suggest that involvement of Kupffer cells in WY-14,643-induced parenchymal cell proliferation and oxidative stress in rodent liver is an acute phenomenon that is not relevant to long-term exposure, but they are still involved in chronic apoptotic responses. These results provide new insight for understanding the mode of hepatocarcinogenic action of peroxisome proliferators.
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599-7431, USA.
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Woods
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Burns
authors.forename: Blair U
authors.initials: BU
authors.lastname: Bradford
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Ross
authors.forename: Oksana
authors.initials: O
authors.lastname: Kosyk
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress; D047493:PPAR alpha / Q000172:deficiency* / Q000235:genetics; D020025:Peroxisome Proliferators / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*
chemical_list: D018797:Cell Cycle Proteins; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C006253:pirinixic acid; D042962:Acyl-CoA Oxidase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D053181:Caspase 8; D053453:Caspase 9