Hwua Y S, Yang J L
Department of Life Sciences, National Tsing Hua University, Taiwan, Republic of China.
Carcinogenesis. 1998 May;19(5):881-8. doi: 10.1093/carcin/19.5.881.
Cadmium and lead have been shown to induce cellular transformations and gene mutations in cultured rodent cells, as well as tumours in live animals. However, the mechanisms by which these metals cause cellular transformations and mutations in human cells have not been explored. In this study, we investigated the abilities of cadmium and lead to induce anchorage-independent transformations and hprt gene mutations in diploid human fibroblasts. Human fibroblasts were exposed to either cadmium acetate (0-60 microM) or lead acetate (0-2 mM) for 24 h. After removal of the metals, the cells were kept in exponential growth for 7 and 9 days before mutation and anchorage-independence assays were taken, respectively. Both cadmium and lead significantly induced anchorage-independent colonies in dose-dependent manners; the frequencies of anchorage-independent colonies induced by these metals were similar to those induced by N-methyl-N'-nitro-N-nitrosoguanidine at approximately equal cytotoxic dose ranges (30-10% survival). 3-Aminotriazole at non-cytotoxic dosages decreased catalase activity by >80%, and markedly enhanced cadmium-induced cytotoxicity and anchorage-independent colonies. Cadmium uptake by human fibroblasts was not affected by 3-aminotriazole co-administered with 10 microM of cadmium; whereas cadmium uptake and accumulation were enhanced 1.5-fold by 3-aminotriazole co-administered with 1-2.5 microM of cadmium. Lead-induced anchorage-independence or cytotoxicity was not affected by 3-aminotriazole co-treatment; however, 3-aminotriazole did significantly enhance lead uptake and accumulation in human fibroblasts. Neither cadmium- nor lead-induced 6-thioguanine-resistant mutation frequency in human fibroblasts. Co-administering these metals with 3-aminotriazole did not enhance mutations in human fibroblasts. These results suggest that cadmium and lead may both act as tumour promoters in diploid human fibroblasts, and that reactive oxygen species is more important in cadmium- than lead-induced cytotoxicity and anchorage-independence.
镉和铅已被证明可在培养的啮齿动物细胞中诱导细胞转化和基因突变，以及在活体动物中诱发肿瘤。然而，这些金属在人类细胞中引起细胞转化和突变的机制尚未得到探索。在本研究中，我们调查了镉和铅在二倍体人成纤维细胞中诱导不依赖贴壁生长转化和hprt基因突变的能力。将人成纤维细胞暴露于醋酸镉（0 - 60微摩尔）或醋酸铅（0 - 2毫摩尔）中24小时。去除金属后，细胞分别在指数生长期培养7天和9天，然后再分别进行突变和不依赖贴壁生长检测。镉和铅均以剂量依赖方式显著诱导不依赖贴壁生长的集落；在大约相同的细胞毒性剂量范围（30% - 10%存活）内，这些金属诱导的不依赖贴壁生长集落频率与N - 甲基 - N' - 硝基 - N - 亚硝基胍诱导的频率相似。非细胞毒性剂量的3 - 氨基三唑使过氧化氢酶活性降低>80%，并显著增强镉诱导的细胞毒性和不依赖贴壁生长的集落。与10微摩尔镉共同给予3 - 氨基三唑时，人成纤维细胞对镉的摄取不受影响；而与1 - 2.5微摩尔镉共同给予3 - 氨基三唑时，镉的摄取和积累增加了1.5倍。3 - 氨基三唑共同处理不影响铅诱导的不依赖贴壁生长或细胞毒性；然而，3 - 氨基三唑确实显著增强了人成纤维细胞对铅的摄取和积累。镉和铅均未诱导人成纤维细胞中6 - 硫鸟嘌呤抗性突变频率。将这些金属与3 - 氨基三唑共同给予并未增强人成纤维细胞中的突变。这些结果表明，镉和铅在二倍体人成纤维细胞中可能均作为肿瘤促进剂起作用，并且活性氧在镉诱导的细胞毒性和不依赖贴壁生长方面比铅诱导的更为重要。
