Woods Courtney G, Burns Amanda M, Maki Akira, Bradford Blair U, Cunningham Michael L, Connor Henry D, Kadiiska Maria B, Mason Ronald P, Peters Jeffrey M, Rusyn Ivan
Department of Environmental Sciences and Engineering, University of North Carolina, 0031 Michael Hooker Research Center, Chapel Hill, NC 27599-7431, USA.
Free Radic Biol Med. 2007 Feb 1;42(3):335-42. doi: 10.1016/j.freeradbiomed.2006.10.053. Epub 2006 Nov 3.
Reactive oxygen species are thought to be crucial for peroxisome proliferator-induced liver carcinogenesis. Free radicals have been shown to mediate the production of mitogenic cytokines by Kupffer cells and cause DNA damage in rodent liver. Previous in vivo experiments demonstrated that acute administration of the peroxisome proliferator di(2-ethylhexyl) phthalate (DEHP) led to an increase in production of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts in liver, an event that was dependent on Kupffer cell NADPH oxidase, but not peroxisome proliferator-activated receptor (PPAR)alpha. Here, we hypothesized that continuous treatment with peroxisome proliferators will cause a sustained formation in POBN radical adducts in liver. Mice were fed diets containing either 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14,643, 0.05% w/w) or DEHP (0.6% w/w) for up to 3 weeks. Liver-derived radical production was assessed in bile samples by measuring POBN radical adducts using electron spin resonance. Our data indicate that WY-14,643 causes a sustained increase in POBN radical adducts in mouse liver and that this effect is greater than that of DEHP. To understand the molecular source of these radical species, NADPH oxidase-deficient (p47phox-null) and PPARalpha-null mice were examined after treatment with WY-14,643. No increase in radicals was observed in PPARalpha-null mice that were treated with WY-14,643 for 3 weeks, while the response in p47phox-nulls was similar to that of wild-type mice. These results show that PPARalpha, not NADPH oxidase, is critical for a sustained increase in POBN radical production caused by peroxisome proliferators in rodent liver. Therefore, peroxisome proliferator-induced POBN radical production in Kupffer cells may be limited to an acute response to these compounds in mouse liver.
活性氧被认为在过氧化物酶体增殖物诱导的肝癌发生过程中起关键作用。自由基已被证明可介导库普弗细胞产生促有丝分裂细胞因子，并导致啮齿动物肝脏中的DNA损伤。先前的体内实验表明，急性给予过氧化物酶体增殖物邻苯二甲酸二（2-乙基己基）酯（DEHP）会导致肝脏中α-（4-吡啶基-1-氧化物）-N-叔丁基硝酮（POBN）自由基加合物的产生增加，这一事件依赖于库普弗细胞NADPH氧化酶，而不依赖于过氧化物酶体增殖物激活受体（PPAR）α。在此，我们假设用过氧化物酶体增殖物持续处理会导致肝脏中POBN自由基加合物的持续形成。给小鼠喂食含有4-氯-6-（2,3-二甲苯胺基）-2-嘧啶硫代乙酸（WY-14,643，0.05% w/w）或DEHP（0.6% w/w）的饲料，持续3周。通过电子自旋共振测量POBN自由基加合物，评估胆汁样本中肝脏衍生的自由基产生情况。我们的数据表明，WY-
