Dorian C, Gattone V H, Klaasen C D
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Toxicol Appl Pharmacol. 1992 Jun;114(2):173-81. doi: 10.1016/0041-008x(92)90066-2.
Chronic, but not acute, exposure to inorganic Cd produces renal damage. However, a single injection of cadmium bound to metallothionein (CdMT) produces renal injury. It is hypothesized that an interorgan redistribution of Cd as CdMT is responsible for the chronic nephrotoxic effect of Cd. To better understand the mechanism(s) of CdMT-induced nephrotoxicity, the intrarenal distribution of 109CdMT was examined. 109CdMT isolated from rat liver was injected into mice at a nonnephrotoxic dose (0.1 mg Cd/kg, iv). The radioactivity in the kidney reached a maximum level (85% of the dose) as early as 30 min following administration and remained essentially constant for up to 7 days after injection. Within the kidney, 109Cd distributed almost entirely to the cortex. Light microscopic autoradiography of the kidney showed that, within the cortex, 109Cd distributed preferentially to the S1 and S2 segments of the proximal convoluted tubules. Within the S1 and S2 segments, the concentration of 109Cd in the basal and apical parts of the cells was similar to that after the nonnephrotoxic dose of CdMT, but after a nephrotoxic dose (0.3 mg Cd/kg) the radioactivity distributed preferentially to the apical portion of the cells. In contrast, light microscopic autoradiography studies with 109CdCl2 revealed that 109Cd was more evenly distributed throughout the proximal tubules. Moreover, after administration of a large dose of inorganic Cd (3 mg Cd/kg), a similar concentration of Cd was found in the convoluted and straight proximal tubules. These data support the hypothesis that CdMT-induced nephrotoxicity might be due, at least in part, to its preferential uptake of CdMT into the S1 and S2 segments of the proximal tubules, the site of Cd-induced nephrotoxicity.
长期而非急性接触无机镉会导致肾脏损伤。然而，单次注射与金属硫蛋白结合的镉（CdMT）会造成肾脏损伤。据推测，作为CdMT的镉在器官间的重新分布是镉产生慢性肾毒性作用的原因。为了更好地理解CdMT诱导肾毒性的机制，研究了¹⁰⁹CdMT在肾脏内的分布情况。将从大鼠肝脏分离得到的¹⁰⁹CdMT以非肾毒性剂量（0.1 mg镉/千克，静脉注射）注入小鼠体内。给药后30分钟内，肾脏中的放射性就达到了最高水平（剂量的85%），并且在注射后长达7天内基本保持恒定。在肾脏内部，¹⁰⁹Cd几乎全部分布在皮质。肾脏的光学显微镜放射自显影显示，在皮质内，¹⁰⁹Cd优先分布在近端曲管的S1和S2节段。在S1和S2节段内，细胞基底和顶端部分的¹⁰⁹Cd浓度与非肾毒性剂量的CdMT注射后的浓度相似，但在肾毒性剂量（0.3 mg镉/千克）注射后，放射性优先分布在细胞的顶端部分。相比之下，¹⁰⁹CdCl₂的光学显微镜放射自显影研究表明，¹⁰⁹Cd在整个近端小管中分布更为均匀。此外，在给予大剂量无机镉（3 mg镉/千克）后，在曲部和直部近端小管中发现了相似浓度的镉。这些数据支持了这样一种假说，即CdMT诱导的肾毒性可能至少部分归因于其优先被近端小管的S1和S2节段摄取，而这正是镉诱导肾毒性的部位。
