Physiological significance of metallothionein on environmental carcinogenesis

为了阐明金属硫蛋白（MT）在环境癌变中的作用，我们利用MT缺失的小鼠（MT的主要亚型MT- i和MT- ii的表达被抑制），研究了MT对7,12 -二甲基苯[a]蒽(DMBA)/12-Οtetradecanoylphorbol-13-acetate （TPA）诱导的两阶段皮肤癌变、口服DMBA诱导的多器官癌变和n -乙基-n -亚硝基脲（ENU）诱导的肺癌的影响。此外，我们还检测了MT-null小鼠对DMBA/TPA、苯并[a]芘（B[a]P）或x射线引起的遗传毒性的易感性。我们发现MT-null小鼠对DMBA/TPA联合用药对皮肤肿瘤的发生率、口服DMBA对胃、肝、肺肿瘤的发生率以及ENU治疗对肺肿瘤的发生率均比野生型小鼠敏感得多。此外，我们在MT-null小鼠和DMBA/TPA联合治疗的野生型小鼠的乳头瘤组织中检测到c-Ha-ras密码子61上A^<182>向T的翻转。用MT缺失小鼠和野生型小鼠实验表明，MT可阻止B[a] p诱导的微核和x射线诱导的DNA氧化损伤和微核。此外，很明显，MT在DMBA/ tpa诱导的两期皮肤癌变的起始和促进阶段都具有抗肿瘤潜力。这些结果提示MT在环境癌变中起着重要的抗癌作用。

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.