Genetic toxicology of lead compounds.
Genetic toxicology of lead compounds.
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先导化合物的遗传毒理学。
DOI：
10.1093/carcin/9.10.1727
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发表时间：
1988
期刊：
影响因子：
4.7
通讯作者：
Rossman,TG
中科院分区：
文献类型：
--
作者：
Zelikoff,JT;Li,JH;Hartwig,A;Wang,XW;Costa,M;Rossman,TG
我们研究了不溶性和可溶性先导化合物在哺乳动物细胞中诱导诱变、细胞转化和姐妹染色单体交换的活性。易被吞噬的不溶性硫化铅对V79细胞的毒性是两种中等可溶性铅化合物的四倍多，尽管可溶性盐的暴露时间长五倍。这些发现证明了金属吸收和生物利用度的不同细胞机制的重要性。在V79细胞中，不溶性硫化铅和更可溶的硝酸铅在HPRT位点处均具有致突变性。虽然较高浓度的硝酸铅致突变性较低，但500 μM浓度的硝酸铅暴露5天后，突变频率比背景高出6倍以上。尽管铅诱导突变的机制尚不清楚，但两种化合物均未能诱导SCE和DNA单链断裂（可通过碱洗脱检测），表明铅诱导的突变可能不是DNA直接损伤的结果，而是可能通过间接机制发生，包括DNA合成和/或修复中重要的酶功能或DNA螺旋结构的干扰。醋酸铅也转化SHE细胞在剂量反应的方式后，48小时的曝光。我们的研究结果表明，铅化合物可能是遗传毒性的间接机制，并提供支持的观点，铅是一种致癌物质。
We have investigated the activity of insoluble and soluble lead compounds in inducing mutagenesis, cell transformation and sister chromatid exchange in mammalian cells. Insoluble lead sulfide, readily phagocytized, was more than four times as toxic to V79 cells on a μM basis, than two moderately soluble lead compounds although the exposure time for the soluble salts was five times longer. These findings demonstrate the importance of different cellular mechanism(s) of metal uptake and bioavailability. Both insoluble lead sulfide and more soluble lead nitrate were mutagenic at the HPRT locus in V79 cells. Although less mutagenic at the higher concentrations, lead nitrate at a concentration of 500 μM enhanced the mutation frequency > 6-fold above background following a 5-day exposure. Although the mechanism(s) by which lead induces mutations is unknown, failure of both compounds to induce SCE and DNA single-strand breaks, detectable by alkaline elution, suggests that lead-induced mutations may not be a result of direct damage to DNA but may occur via indirect mechanisms including disturbances in enzyme functions important in DNA synthesis and/or repair, or in DNA-helical structure. Lead acetate also transformed SHE cells in a dose-response fashion following a 48-h exposure. Our results indicate that lead compounds may be genotoxic by an indirect mechanism, and lend support to the view that lead is a carcinogen.