Dorian C, Gattone V H, Klaassen C D
Department of Pharmacology, University of Kansas Medical Center, Kansas City 66160.
Toxicol Appl Pharmacol. 1992 Dec;117(2):242-8. doi: 10.1016/0041-008x(92)90243-l.
Of major concern in Cd toxicity is its ability to produce renal damage after chronic exposure in humans and experimental animals. Renal injury affects predominantly the proximal tubules and more specifically the first segments of these tubules. Similar toxic effects to the kidneys are observed after administration of cadmium bound to metallothionein (CdMT). Therefore, CdMT was used in this study as a model to understand the mechanism(s) of Cd nephrotoxicity. It has been recently demonstrated that Cd from CdMT was preferentially taken up by the proximal convoluted tubules. Therefore, the purpose of these studies was to determine if the organic portion of the complex was also accumulated in these tubules. [35S]CdMT prepared from rat liver was administered intravenously to mice at a nonnephrotoxic dose (0.1 mg Cd/kg). The radioactivity in the kidney showed maximum level (80% of the dose) 15 min after the injection. This preferential renal uptake was also observed after administration of various doses of [35S]CdMT. In contrast to the earlier observed persistency of 109Cd in the kidney after 109CdMT administration, 35S disappeared rapidly (with a half-life of approximately 2 hr), and 24 hr after injection of [35S]CdMT, there was very little 35S left in the kidneys. These observations indicate that the protein portion of CdMT is rapidly degraded after renal uptake of CdMT and the released Cd is retained in the kidney. Within the kidney, 35S distributed mainly to the cortex. Light microscopic autoradiography showed that [35S]CdMT preferentially distributed to the proximal convoluted tubule (S1 and S2), which is the site of nephrotoxicity. Within the S1 and S2 segments, a greater distribution of 35S to the apical portion of the cells was observed after administration of both a nonnephrotoxic (0.1 mg Cd/kg) and a nephrotoxic (0.3 mg Cd/kg) dose. 109Cd administered as 109CdMT also distributed to the apical portion of the S1 and S2 cells. Therefore, both the organic (35S) and inorganic (109Cd) portions of CdMT are rapidly and efficiently taken up by the S1 and S2 cells of the proximal tubules, the site of nephrotoxicity. These observations support the concept that CdMT is readily taken up by the proximal tubular cells as a complex, and then its protein portion is rapidly degraded to release Cd that binds permanently to intracellular sites and produces nephrotoxicity.
镉毒性的主要问题在于，在人类和实验动物中长期接触后，它有能力导致肾脏损伤。肾脏损伤主要影响近端小管，更具体地说是这些小管的起始段。给予与金属硫蛋白结合的镉（CdMT）后，也观察到了对肾脏的类似毒性作用。因此，在本研究中使用CdMT作为模型来了解镉肾毒性的机制。最近已证明，CdMT中的镉优先被近端曲管摄取。因此，这些研究的目的是确定该复合物的有机部分是否也在这些小管中积累。将从大鼠肝脏制备的[35S]CdMT以非肾毒性剂量（0.1mg镉/千克）静脉注射给小鼠。注射后15分钟，肾脏中的放射性达到最高水平（剂量的80%）。给予不同剂量的[35S]CdMT后，也观察到了这种肾脏优先摄取现象。与早期观察到的给予109CdMT后109Cd在肾脏中持续存在不同，35S迅速消失（半衰期约为2小时），注射[35S]CdMT后24小时，肾脏中几乎没有35S残留。这些观察结果表明，CdMT的蛋白质部分在肾脏摄取CdMT后迅速降解，释放出的镉保留在肾脏中。在肾脏内，35S主要分布在皮质。光学显微镜放射自显影显示，[35S]CdMT优先分布在近端曲管（S1和S2），这是肾毒性的部位。在给予非肾毒性（0.1mg镉/千克）和肾毒性（0.3mg镉/千克）剂量后，在S1和S2段内，观察到35S更多地分布在细胞的顶端部分。作为109CdMT给予的109Cd也分布在S1和S2细胞的顶端部分。因此，CdMT的有机（35S）和无机（109Cd）部分都被近端小管的S1和S2细胞迅速而有效地摄取，这是肾毒性的部位。这些观察结果支持了这样一种概念，即CdMT作为一种复合物很容易被近端小管细胞摄取，然后其蛋白质部分迅速降解以释放出镉，镉与细胞内位点永久结合并产生肾毒性。
