Isobe Kaori, Ito Tsuneo, Komatsu Shun-Ichiro, Asanuma Kentaro, Fujii Etsuko, Kato Chie, Adachi Kenji, Kato Atsuhiko, Sugimoto Tetsuro, Suzuki Masami
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
J Toxicol Pathol. 2012 Dec;25(4):281-5. doi: 10.1293/tox.25.281. Epub 2012 Dec 20.
Increased incidence of adrenal pheochromocytoma is frequently encountered in rat carcinogenicity studies. In some of the studies, the finding is judged to be due to a rat-specific mechanism of carcinogenesis caused by a disturbance of calcium homeostasis. However, direct evidence that the proliferation of chromaffin cells in the adrenal medulla is induced solely by hypercalcemia is not available. In this study, calcium gluconate was intravenously infused for 7 days to rat chromaffin cells by a tail cuff method, and cumulative labeling with bromodeoxyuridine (BrdU) was carried out to evaluate the proliferative activity. The serum calcium concentration was dose-dependently increased, and a high calcium concentration was stably sustained from day 2 to 7. In the adrenal medulla, BrdU-positive chromaffin cells increased in the calcium gluconate-treated animals, and the BrdU-labeling index increased in a dose-dependent manner. In addition, an increased BrdU-labeling index of chromaffin cells was shown to correlate with the serum calcium concentration. Our results demonstrate that hypercalcemia directly enhances the proliferative activity of chromaffin cells and that the proliferative activity is correlated with the serum calcium concentration.
在大鼠致癌性研究中，肾上腺嗜铬细胞瘤的发病率增加屡见不鲜。在一些研究中，这一发现被判定是由于钙稳态紊乱引发的大鼠特异性致癌机制所致。然而，尚无直接证据表明肾上腺髓质嗜铬细胞的增殖完全是由高钙血症诱导的。在本研究中，采用尾套法给大鼠嗜铬细胞静脉输注葡萄糖酸钙7天，并进行溴脱氧尿苷（BrdU）累积标记以评估增殖活性。血清钙浓度呈剂量依赖性升高，且从第2天到第7天一直稳定维持在高钙浓度水平。在肾上腺髓质中，葡萄糖酸钙处理组动物的BrdU阳性嗜铬细胞增多，且BrdU标记指数呈剂量依赖性增加。此外，嗜铬细胞BrdU标记指数的增加与血清钙浓度相关。我们的结果表明，高钙血症直接增强嗜铬细胞的增殖活性，且增殖活性与血清钙浓度相关。
