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，本研究观察了MT对7，12-二甲基苯并[a]蒽（DMBA）/12-O十四酰佛波醇-13-乙酸酯（TPA）诱发的两阶段皮肤癌的影响，采用MT基因敲除小鼠，观察DMBA诱导的多器官癌变和N-乙基-N-亚硝基脲（ENU）诱导的肺癌的发生，II，MT的主要亚型，被抑制。此外，我们还检测了MT基因敲除小鼠对DMBA/TPA、苯并[a]芘（B[a]P）或X射线引起的遗传毒性的敏感性，发现MT基因敲除小鼠对DMBA/TPA组合引起的皮肤肿瘤的发生率、DMBA口服给药引起的胃、肝和肺肿瘤的发生率以及ENU治疗引起的肺肿瘤的发生率比野生型小鼠敏感得多。我们检测到<182>MT敲除小鼠和接受DMBA/TPA联合治疗的野生型小鼠乳头状瘤组织中c-Ha-ras第61密码子A^至T的颠换。MT对B[a] P诱发的微核和X射线诱发的DNA氧化损伤及微核均有明显的抑制作用。此外，MT在DMBA/TPA诱导的两阶段皮肤癌发生的起始阶段和促进阶段均具有抗肿瘤作用，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.