Lermioglu F, Bernard A
Unit of Industrial Toxicology and Occupational Medicine, Faculty of Medicine, Catholic University of Louvain, Brussels, Belgium.
Toxicol Lett. 1998 Mar 16;95(1):9-13. doi: 10.1016/s0378-4274(98)00016-2.
Recent reports indicate that calmodulin inhibitors (CIs) can modify cadmium (Cd) toxicity in rodents. Pretreatment with CIs prevents Cd-induced testicular damage in mice and reduces the severity of such damage in rats. On the other hand it has been suggested that the cellular transport of Cd can be partly inhibited by the calcium-channel inhibitor, verapamil. The aim of this study was to determine whether these inhibitors can prevent the toxic effects of Cd on the kidney which is the critical organ. For that purpose, we have examined the effects of two CIs (trifluoperazine and chlorpromazine) and of verapamil on the development of tubular damage in female Sprague-Dawley rats. The animals were injected subcutaneously 5 days a week for 8 weeks with cadmium chloride (1 mg Cd/kg), alone or in association with trifluoperazine (20 mg/kg), chlorpromazine (15 mg/kg) or verapamil (2 x 5 mg/kg). The development of renal dysfunction was followed by measuring the urinary excretion of the low molecular weight protein Clara cell protein (CC16). In Cd-treated rats, the urinary excretion of CC16 started to increase from week 6 to reach at the end of experiment values more than 100-times above normal. CIs or verapamil did not influence the rise of urinary CC16 induced by Cd. The three inhibitors, by contrast, enhanced the accumulation of Cd in the liver and, at the exception of chlorpromazine, in the kidneys of Cd-treated rats. Although interfering with the metabolism of Cd, CIs and verapamil do not prevent renal damage in rats chronically exposed to this heavy metal.
最近的报告表明，钙调蛋白抑制剂（CIs）可以改变啮齿动物体内镉（Cd）的毒性。用CIs预处理可预防镉诱导的小鼠睾丸损伤，并减轻大鼠此类损伤的严重程度。另一方面，有人提出钙通道抑制剂维拉帕米可部分抑制镉的细胞转运。本研究的目的是确定这些抑制剂是否能预防镉对关键器官——肾脏的毒性作用。为此，我们研究了两种CIs（三氟拉嗪和氯丙嗪）以及维拉帕米对雌性斯普拉格-道利大鼠肾小管损伤发展的影响。这些动物每周皮下注射5天，持续8周，注射氯化镉（1毫克镉/千克），单独注射或与三氟拉嗪（20毫克/千克）、氯丙嗪（15毫克/千克）或维拉帕米（2×5毫克/千克）联合注射。通过测量低分子量蛋白克拉拉细胞蛋白（CC16）的尿排泄量来跟踪肾功能障碍的发展。在镉处理的大鼠中，CC16的尿排泄量从第6周开始增加，在实验结束时达到比正常水平高出100多倍的值。CIs或维拉帕米并未影响镉诱导的尿CC16升高。相比之下，这三种抑制剂增加了镉在镉处理大鼠肝脏中的蓄积，除氯丙嗪外，还增加了在肾脏中的蓄积。尽管CIs和维拉帕米干扰了镉的代谢，但它们并不能预防长期接触这种重金属的大鼠的肾脏损伤。
