GENOTOXIC PROPERTIES OF 4-HYDROXYALKENALS AND ANALOGOUS ALDEHYDES
GENOTOXIC PROPERTIES OF 4-HYDROXYALKENALS AND ANALOGOUS ALDEHYDES
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DOI：
10.1016/0027-5107(93)90158-c
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发表时间：
1993-12-01
期刊：
影响因子：
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通讯作者：
ESTERBAUER, H
中科院分区：
文献类型：
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作者：
ECKL, PM;ORTNER, A;ESTERBAUER, H
4-羟基壬烯醛（HNE）是脂质过氧化的主要产物之一，已被证明在微摩尔范围内诱导遗传毒性效应。HNE具有太多的结构域，亲脂性尾部和具有三个官能团的极性头部：醛和羟基以及反式CC双键。为了评价其相对重要性，将HNE的遗传毒性效应与同源醛4-羟基己烯醛和4-羟基十一烯醛（不同长度的亲脂性尾）以及类似醛2-反式壬烯醛（缺乏OH基团）和壬醛（缺乏OH基团和反式CC双键）的遗传毒性效应进行了比较。为了进一步确定生物转化和/或解毒反应的影响，对成年大鼠肝细胞的原代培养物进行了研究。HNE处理3小时，在浓度大于或等于0.1 μ M时诱导统计学显著水平的SCE，在浓度大于或等于1 μ M时诱导微核，在浓度为10 μ M时诱导染色体畸变。与HNE相比，同源醛在较高浓度下诱导了显着的遗传毒性效应。SCE频率在浓度大于或等于1 μ M的4-羟基十一烯醛和浓度为10 μ M的4-羟基己烯醛中得到统计学上显著的增加。在4-羟基己烯醛和4-羟基十一烯醛的浓度分别大于或等于10 μ M和10 μ M时，染色体畸变的诱导显著升高。HNE类似物醛2-trans-nonenal和壬醛在浓度大于或等于1 μ M（壬醛）和大于或等于10 μ M（2-trans-nonenal）时诱导的SCE频率具有统计学显著性。未证明对染色体畸变或微核有显著诱导作用。研究的醛类结构似乎以下列方式影响细胞毒性和遗传毒性潜力。(1)亲脂性尾部的长度对染色体畸变诱导没有影响，但似乎决定了SCE和微核的产率以及细胞毒性潜力。(2)OH基团（2-反式-壬烯醛）的缺乏降低了醛的SCE诱导潜力，使剂量-效应曲线向更高浓度移动。与HNE诱导的SCE相比，形状相似，表明可能形成了相同的活性代谢产物。(3)OH基团和CC双键（壬醛）的缺乏不会导致SCE诱导活性的完全丧失。剂量-反应曲线的不同形状表明不同的代谢和/或与DNA相互作用的不同模式。
4-Hydroxynonenal (HNE), one of the major products of lipid peroxidation, has been demonstrated to induce genotoxic effects in the micromolar range. HNE has too structural domains, a lipophilic tail and a polar head with three functional groups: the aldehyde and hydroxy groups and the trans CC double bond. To evaluate their relative importance, the genotoxic effects of HNE were compared with those of the homologous aldehydes 4-hydroxyhexenal and 4-hydroxyundecenal (different lengths of the lipophilic tail), and the analogous aldehydes 2-trans-nonenal (lacking the OH group) and nonanal (lacking the OH group and the trans CC double bond). This investigation was carried out on primary cultures of adult rat hepatocytes in order to further determine the influence of biotransformation- and/or detoxification reactions.A 3-h treatment with HNE induces statistically significant levels of SCE at concentrations greater-than-or-equal-to 0.1 muM, micronuclei at concentrations greater-than-or-equal-to 1 muM and chromosomal aberrations at a concentration of 10 muM. Compared to HNE the homologous aldehydes induced a significant genotoxic effect at higher concentrations. Statistically significant increases in SCE frequency were obtained at concentrations greater-than-or-equal-to 1 muM for 4-hydroxyundecenal and at a concentration of 10 muM for 4-hydroxyhexenal. The induction of chromosomal aberrations was significantly elevated at concentrations of greater-than-or-equal-to 10 muM and 10 muM for 4-hydroxyhexenal and 4-hydroxyundecenal, respectively. Except for a 4-hydroxyhexenal concentration of 1 muM, both aldehydes did not induce statistically significant levels of micronuclei.The HNE analogous aldehydes 2-trans-nonenal and nonanal induced statistically significant frequencies of SCE at concentrations, of greater-than-or-equal-to 1 muM (nonanal) and greater-than-or-equal-to 10 muM (2-trans-nonenal). No significant induction of chromosomal aberrations or micronuclei could be demonstrated.The structure of the aldehydes investigated appears to influence the cyto- and genotoxic potential in the following ways. (1) The length of the lipophilic tail has no influence on chromosomal aberration induction, but appears to determine the yield of SCE and micronuclei, and the cytotoxic potential. (2) The lack of the OH group (2-trans-nonenal) reduces the SCE-inducing potential of the aldehyde shifting the dose-effect curve to higher concentrations. The similar shape compared to SCE induction by HNE indicates that possibly the same active metabolite is formed. (3) The lack of both the OH group and the CC double bond (nonanal) does not result in a complete loss of the SCE-inducing activity. The different shape of the dose-response curve suggests a different metabolism and/or a different mode of interaction with DNA.