Coogan T P, Shiraishi N, Waalkes M P
Inorganic Carcinogenesis Section, National Cancer Institute, Frederick, Maryland 21702-1201, USA.
Toxicol Appl Pharmacol. 1995 May;132(1):164-73. doi: 10.1006/taap.1995.1097.
Metallothionein (MT), a high-affinity metal-binding protein, is known to detoxicate cadmium and may play an important role in cadmium carcinogenesis. In the rat, the ventral lobe of the prostate is sensitive to cadmium carcinogenesis, while the dorsolateral lobe is refractory. The possibility exists that the basis of this lobe-specific sensitivity may lie in the expression of the MT gene. Thus, the expression of the MT gene in lobes of the rat prostate was studied and, for comparative purposes, the expression of the MT gene in the liver, a tissue with well-defined high activity, was also assessed. MT gene expression was determined using a cDNA probe specific for MT-I, oligonucleotide probes specific for MT-I and MT-II, and an assay for cadmium-binding protein capacity. Basal levels of MT-I mRNA and cadmium-binding protein were much less in the ventral prostate than in the liver or dorsolateral prostate. Cadmium, given at a dose known to induce tumors of the ventral prostate (2.5 mumol/kg, sc), did not result in an increase in MT gene expression in the ventral prostate, as assessed by cadmium-binding protein levels or MT-I mRNA, over 72 hr. Small elevations of cadmium-binding protein capacity were detected at high doses of cadmium (25 and 40 mumol/kg) in the ventral prostate but no corresponding increases in MT mRNA were seen. In sharp contrast, hepatic MT gene expression was highly activated throughout the dosage range. Dose-response analysis 24 hr after cadmium administration (0.25 to 40 mumol/kg, sc) showed that MT-I and MT-II mRNA levels were increased in liver in a dose-dependent manner, while no evidence was found for MT gene activation in ventral prostate. In the dorsolateral prostate the high basal activity of the MT gene was shown, as assessed by MT-I and MT-II mRNA levels, which was not further elevated by cadmium treatments. Cadmium accumulation was much lower in the ventral prostate than in the liver. However, levels of cadmium that were sufficient to activate the hepatic MT gene had, in fact, reached the ventral prostate. Thus, the poor basal expression and lack of activation of the MT gene within the ventral lobe of the rat prostate may be the genetic basis to this tissue's sensitivity to the carcinogenic effects of cadmium.
金属硫蛋白（MT）是一种高亲和力的金属结合蛋白，已知其可使镉解毒，并可能在镉致癌过程中发挥重要作用。在大鼠中，前列腺腹叶对镉致癌敏感，而背外侧叶则具有抗性。这种叶特异性敏感性的基础可能在于MT基因的表达。因此，研究了大鼠前列腺各叶中MT基因的表达，并且为了进行比较，还评估了肝脏（一种具有明确高活性的组织）中MT基因的表达。使用针对MT-I的cDNA探针、针对MT-I和MT-II的寡核苷酸探针以及镉结合蛋白能力测定法来确定MT基因的表达。腹侧前列腺中MT-I mRNA和镉结合蛋白的基础水平远低于肝脏或背外侧前列腺。以已知可诱发腹侧前列腺肿瘤的剂量（2.5 μmol/kg，皮下注射）给予镉，在72小时内，通过镉结合蛋白水平或MT-I mRNA评估，腹侧前列腺中MT基因的表达并未增加。在腹侧前列腺中，高剂量镉（25和40 μmol/kg）时检测到镉结合蛋白能力有小幅升高，但未见MT mRNA相应增加。与之形成鲜明对比的是，在整个剂量范围内肝脏MT基因表达均被高度激活。镉给药（0.25至40 μmol/kg，皮下注射）24小时后的剂量反应分析表明，肝脏中MT-I和MT-II mRNA水平呈剂量依赖性增加，而在腹侧前列腺中未发现MT基因激活的证据。通过MT-I和MT-II mRNA水平评估，在背外侧前列腺中显示出MT基因的高基础活性，镉处理并未使其进一步升高。腹侧前列腺中的镉蓄积远低于肝脏。然而，实际上足以激活肝脏MT基因的镉水平已到达腹侧前列腺。因此，大鼠前列腺腹叶中MT基因的低基础表达和缺乏激活可能是该组织对镉致癌作用敏感的遗传基础。
