Effect of the peroxisome proliferator ciprofibrate on lipid peroxidation and 8-hydroxydeoxyguanosine formation in transgenic mice with elevated hepatic catalase activity.
Effect of the peroxisome proliferator ciprofibrate on lipid peroxidation and 8-hydroxydeoxyguanosine formation in transgenic mice with elevated hepatic catalase activity.
复制标题
过氧化物酶体增殖剂环丙贝特对肝过氧化氢酶活性升高的转基因小鼠中脂质过氧化和 8-羟基脱氧鸟苷形成的影响。
DOI：
10.1016/s0891-5849(98)00007-0
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发表时间：
1998
影响因子：
7.4
通讯作者：
Glauert,HP
中科院分区：
文献类型：
--
作者：
Nilakantan,V;Spear,BT;Glauert,HP
过氧化物酶体增殖物是一类非遗传毒性的肝脏致癌物，其作用机制是增加肝脏的氧化损伤。为了验证这一假设，我们已经产生了一个转基因小鼠品系，其具有升高的过氧化氢酶活性，特别是在肝脏中。在这项研究中，我们研究了过氧化氢酶过度表达是否影响脂质过氧化或氧化性DNA损伤的诱导，这两种机制已被假设为是重要的过氧化物酶体增殖物的致癌作用。给转基因小鼠或非转基因同窝小鼠喂食0.01%环丙贝特或对照饮食21天。过氧化氢酶过表达对脂酰辅酶A氧化酶和月桂酸羟化酶活性没有显著影响，但转基因动物中脂酰辅酶A氧化酶与过氧化氢酶的比例显著降低。通过定量丙二醛和共轭二烯的浓度来估计肝脏脂质过氧化。环丙贝特治疗不影响任一终点，但过氧化氢酶过表达增加了丙二醛（仅在未治疗的小鼠中）和共轭二烯（在未治疗和环丙贝特喂养的小鼠中）的浓度。通过高效液相色谱/电化学检测定量8-羟基脱氧鸟苷（8-OHdG）来估计氧化性DNA损伤。环丙贝特治疗显著增加肝脏8-OHdG浓度，与先前的几项研究一致，但过氧化氢酶过表达并没有显著影响它们，尽管在未治疗的小鼠中8-OHdG浓度降低了50%。这些结果表明，过氧化氢酶代谢过氧化氢是不是一个重要因素的发展，肝脏脂质过氧化。未处理的转基因小鼠中肝脏8-OHdG的减少和环丙贝特给药后观察到的增加表明过氧化氢在8-OHdG的形成中很重要。虽然环丙贝特处理的转基因小鼠中8-OHdG水平没有下降并不支持这一结论，但过氧化氢酶水平可能不足以影响这一终点。可能需要具有更高肝过氧化氢酶活性的转基因小鼠来解决这个问题。
Peroxisome proliferators are a group of non-genotoxic hepatic carcinogens which have been proposed to act by increasing oxidative damage in the liver. To test this hypothesis, we have produced a transgenic mouse line that has elevated catalase activity specifically in the liver. In this study, we have examined if catalase overexpression influences the induction of lipid peroxidation or oxidative DNA damage, two mechanisms which have been hypothesized to be important in the carcinogenesis by peroxisome proliferators. Transgenic mice or non-transgenic litter mates were fed either 0.01% ciprofibrate or a control diet for 21 days. The activities of fatty acyl CoA oxidase and lauric acid hydroxylase were not significantly affected by catalase overexpression, although the ratio of fatty acyl CoA oxidase to catalase was significantly decreased in transgenic animals. Hepatic lipid peroxidation was estimated by quantifying the concentrations of malondialdehyde and conjugated dienes. Ciprofibrate treatment did not affect either endpoint, but catalase overexpression increased the concentrations of malondialdehyde (in untreated mice only) and conjugated dienes (in both untreated and ciprofibrate-fed mice). Oxidative DNA damage was estimated by quantifying 8-hydroxydeoxyguanosine (8-OHdG) by high-performance liquid chromatography/electrochemical detection. Ciprofibrate treatment significantly increased hepatic 8-OHdG concentrations, in agreement with several previous studies, but catalase overexpression did not significantly affect them, although 8-OHdG concentrations were decreased 50% in untreated mice. These results imply that the metabolism of hydrogen peroxide by catalase is not an important factor in the development of hepatic lipid peroxidation. The decrease in hepatic 8-OHdG in untreated transgenic mice and the increase seen after ciprofibrate administration imply that hydrogen peroxide is important in the formation of 8-OHdG. While the lack of decreased 8-OHdG levels in ciprofibrate-treated transgenic mice does not support this conclusion, it is possible that catalase levels were not sufficiently high to affect this endpoint. Transgenic mice with higher hepatic catalase activities may be required to resolve this issue.