Formation of 8-hydroxydeoxyguanosine in liver DNA of rats following long-term exposure to a peroxisome proliferator.
Formation of 8-hydroxydeoxyguanosine in liver DNA of rats following long-term exposure to a peroxisome proliferator.
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发表时间：
1989-05
期刊：
影响因子：
11.2
通讯作者：
H. Kasai;Y. Okada;S. Nishimura;M. Rao;Janardan K. Reddy
中科院分区：
文献类型：
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作者：
H. Kasai;Y. Okada;S. Nishimura;M. Rao;Janardan K. Reddy
非遗传毒性的过氧化物体增殖物诱导大鼠和小鼠肝细胞癌的机制仍然耐人寻味。现有的实验证据表明，过氧化物体的增殖和诱导过氧化物体相关的酶导致氧化应激，进而导致肿瘤的发生。然而，到目前为止，还没有直接的证据表明过氧化物酶增殖物处理的动物肝脏中存在DNA氧化损伤。在本研究中，我们检测了用环丙贝特处理大鼠肝脏获得的DNA，环丙贝特是一种有效的过氧化体增殖剂，用于8-羟基脱氧鸟苷(8-OH-DG)的不同时间段，8-羟基脱氧鸟苷(8-OH-DG)是一种由羟基自由基导致DNA损伤的加合物。在饮食中给予浓度为0.025%的环丙贝特16周、28周、36周或40周后，8-OH-dG水平逐渐升高。在环丙贝特治疗16周、28周和40周时，与对照组相比，肝DNA中的8-OH-DG显著增加。这种8-OH-dG水平的增加归因于慢性环丙贝特治疗导致的持续的过氧化物体增殖，因为在接受单次大剂量环丙贝特治疗的大鼠肝DNA中没有发现8-OH-dG的增加。这项研究的结果首次清楚地表明，过氧化物体的持续增殖会导致特定的DNA氧化损伤。
The mechanism by which nongenotoxic peroxisome proliferators induce hepatocellular carcinomas in rats and mice remains intriguing. The available experimental evidence suggests that the proliferation of peroxisomes and induction of peroxisome-associated enzymes results in oxidative stress which then leads to tumorigenesis. However, so far no direct evidence for oxidative DNA damage in livers of peroxisome proliferator-treated animals has been established. In the present study we have examined the DNA obtained from the livers of rats treated with ciprofibrate, a potent peroxisome proliferator, for variable periods of time for 8-hydroxydeoxyguanosine (8-OH-dG), an adduct that results from the damage of DNA caused by hydroxyl radical. Administration of ciprofibrate in diet at a concentration of 0.025% for 16, 28, 36, or 40 weeks resulted in progressive increases in the levels of 8-OH-dG. At 16, 28, and 40 weeks of ciprofibrate treatment, the 8-OH-dG in the liver DNA was significantly increased as compared to controls. This increase in 8-OH-dG levels is attributed to persistent peroxisome proliferation resulting from chronic ciprofibrate treatment as no increase in 8-OH-dG was found in liver DNA of rats that received a single large dose of ciprofibrate. The results of this study clearly demonstrate, for the first time, that persistent proliferation of peroxisomes leads to specific oxidative DNA damage.