Foulkes E C, Blanck S
Department of Environmental Health, University of Cincinnati College of Medicine, Ohio 45267-0056.
Toxicol Appl Pharmacol. 1991 Mar 15;108(1):150-6. doi: 10.1016/0041-008x(91)90278-m.
The objective of this investigation was to determine whether Cd inhibition of amino acid transport across basolateral (BL) cell membranes in renal tubules results from a direct toxic action at that site. The concentration ratio (R) of cycloleucine in cell water/arterial plasma at steady state in nonfiltering rabbit kidneys consistently exceeded 1.0, thus confirming the active nature of BL amino acid uptake. BL cycloleucine extrusion, though down the concentration gradient, has previously been shown to be greatly slowed in Cd-poisoned animals; nevertheless, R remained unchanged. Active uptake and passive extrusion of cycloleucine must therefore be equally sensitive to Cd, a fact strongly suggesting an indirect action of the metal on BL solute transfer. This hypothesis is strengthened by the observation that R for paraaminohippurate (PAH), another solute actively accumulated across BL membranes, also remained unaffected by Cd poisoning. The reduction in R(PAH) by the direct transport inhibitor probenecid served as positive control. The additional finding that R(cycloleucine) is also depressed by probenecid, as well as by excess PAH, indicates some overlap in substrate specificities of the two carrier systems. The systems are not identical, however, as can be deduced from the observation that L-leucine affected only transport of cycloleucine, not that of PAH.
本研究的目的是确定肾小管基底外侧（BL）细胞膜上镉对氨基酸转运的抑制是否源于该位点的直接毒性作用。在未滤过的兔肾中，稳态时细胞内水/动脉血浆中环亮氨酸的浓度比（R）始终超过1.0，从而证实了BL氨基酸摄取的活性性质。此前已表明，尽管BL环亮氨酸的外排是顺着浓度梯度的，但在镉中毒的动物中其外排速度大大减慢；然而，R保持不变。因此，环亮氨酸的主动摄取和被动外排对镉的敏感性必定相同，这一事实强烈表明该金属对BL溶质转运有间接作用。对另一种通过BL膜主动积累的溶质对氨基马尿酸（PAH）而言，其R也不受镉中毒影响，这一观察结果进一步支持了这一假说。直接转运抑制剂丙磺舒使R（PAH）降低，作为阳性对照。另外还发现，丙磺舒以及过量的PAH也会使R（环亮氨酸）降低，这表明两种载体系统在底物特异性上存在一定重叠。然而，这两个系统并不相同，从L-亮氨酸仅影响环亮氨酸的转运而不影响PAH的转运这一观察结果可以推断出来。
