Woods Courtney G, Burns Amanda M, Bradford Blair U, Ross Pamela K, Kosyk Oksana, Swenberg James A, Cunningham Michael L, Rusyn Ivan
Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599-7431, USA.
Toxicol Sci. 2007 Aug;98(2):366-74. doi: 10.1093/toxsci/kfm104. Epub 2007 May 5.
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.
长期将啮齿动物暴露于过氧化物酶体增殖剂会导致过氧化物酶体增加、肝细胞增殖、氧化损伤、细胞凋亡受抑制，最终导致肝腺瘤和肝癌的发生。过氧化物酶体增殖物激活受体（PPAR）α被证明是这些多效性反应所必需的；然而，库普弗细胞（肝脏常驻巨噬细胞）也被确定在过氧化物酶体增殖剂诱导的效应中发挥作用，且独立于PPARα。先前的研究表明，烟酰胺腺嘌呤二核苷酸磷酸（还原型）[NADPH]氧化酶产生的氧化剂介导了过氧化物酶体增殖剂对啮齿动物肝脏的急性效应。为了确定库普弗细胞氧化剂是否也参与慢性效应，将NADPH氧化酶缺陷（p47（phox）基因敲除）小鼠与Pparα基因敲除小鼠和野生型小鼠一起喂食含4-氯-6-（2,3-二甲基苯胺基）-2-嘧啶硫代乙酸（WY-14,643）的饲料（0.1%重量/重量）1周、5周或5个月。正如预期的那样，在Pparα基因敲除小鼠中未观察到肝脏大小、细胞复制率或过氧化物酶体增殖剂的其他表型效应有变化。经过5个月的治疗，p47（phox）基因敲除小鼠和野生型小鼠表现出过氧化物酶体增殖剂诱导的不良肝脏效应，同时氧化DNA损伤增加和细胞增殖增加，这种反应可能是通过核因子κB（NFkB）介导的。WY-14,643引起的细胞凋亡受抑制依赖于NADPH氧化酶和PPARα。总的来说，这些发现表明，库普弗细胞参与WY-14,643诱导的啮齿动物肝脏实质细胞增殖和氧化应激是一种急性现象，与长期暴露无关，但它们仍参与慢性凋亡反应。这些结果为理解过氧化物酶体增殖剂的肝癌致癌作用模式提供了新的见解。
