Physiological significance of metallothionein on environmental carcinogenesis

为探讨金属硫蛋白(MT)在环境致癌中的作用，我们采用MT基因缺失的小鼠，通过抑制MT主要亚型MT-I和MT-II的表达，观察了MT对7，12-二甲基苯并[a]菲/12-二甲基苯并[a]菲/12-二甲基苯并菲-13-醋酸酯(TPA)诱发的两阶段皮肤癌、DMBA口服诱发的多脏器癌变和N-乙基-N-亚硝脲(ENU)诱发的肺癌的影响。此外，我们还观察了MT缺失型小鼠对DMBA/TPA、苯并[a]吡喃(B[a]P)和X射线照射所致遗传毒性的敏感性。MT缺失型小鼠对DMBA/TPA联合作用引起的皮肤肿瘤的发生率、DMBA口服给药引起的胃、肝、肺肿瘤的发生率以及ENU治疗引起的肺癌发生率均比野生型小鼠敏感得多。MT缺失型小鼠和DMBA/TPA联合治疗的野生型小鼠乳头状瘤组织中c-Ha-ras基因61位密码子的T。MT缺失型小鼠和野生型小鼠实验结果表明，MT对苯并[a]P诱发的小鼠微核和X射线照射所致的DNA氧化损伤和微核均有保护作用。此外，MT在DMBA/TPA诱导的两阶段皮肤癌的起始和促进阶段均具有一定的抗癌活性，提示MT在环境致癌过程中起重要的抗癌作用。

To elucidate the role of metallothionein (MT) in the environmental carcinogenesis, we examined the effect of MT on the two-stage skin carcinogenesis induced by 7, 12-dimethylbenz[a]anthracene (DMBA)/12-Οtetradecanoylphorbol-13-acetate (TPA), multiple organs carcinogenesis induced by DMBA oral administration and lung carcinogenesis induced by N-ethyl-N-nitrosourea (ENU) using MT-null mice whose expression of MT-I and MT-II, major isoforms of MT, were suppressed. In addition, we also eximined the susceptibility of MT-null mice in the genotoxicity caused by DMBA/TPA, benzo[a]pyren (B[a]P) or X-irradiation.MT-null mice were found to be much more sensitive than wild-type mice to incidence of skin tumor by DMBA/TPA combination, incidence of tumors in the stomach, liver and lung by DMBA oral administration and incidence of lung tumor by ENU treatment.Moreover, we detected transversion of A^<182> to T in codon 61 of c-Ha-ras in papilloma tissues of MT-null mice and wild-type mice treated with DMBA/TPA combination. It was showed using MT-null mice and wild-type mice that MT prevented B[a]P-induced micronucleus and X-irradiation-induced oxidative DNA damage and micronucleus. In addition, it was clear that MT has antitumorigenic potential in both the initiation and promotion stage of DMBA/TPA-induced two-stage skin carcinogenesis.These results suggest that MT plays an important role as anticarcinogenic factor in environmental carcinogenesis.