Sauvant C, Silbernagl S, Gekle M
Physiologisches Institut, Universität Würzburg, Würzburg, Germany.
J Pharmacol Exp Ther. 1998 Oct;287(1):13-20.
Ochratoxin A (OTA) is a widespread mycotoxin, which is nephrotoxic and carcinogenic. Because a decline in net-secretion of para-aminohippuric acid (PAH) was observed after chronic OTA exposition in vivo, we investigated the effect of OTA on proximal-tubule-derived opossum kidney (OK) cells. OTA up to 10(-5) mol/liter had no acute effect on PAH transport when bovine serum albumin (BSA) was present. By contrast, 72-hr incubation of OK cells led to a decrease of PAH transport with half-maximal inhibition at 6 . 10(-7) mol/liter for transepithelial secretion and 6 . 10(-8) mol/liter for basolateral uptake of PAH. Incubation of OK cells with 10(-6) mol/liter OTA for 72 hr reduced the affinity of PAH uptake, and decreased the maximum secretion rate to one-fifth of control values. Apical uptake of amino acids and basolateral uptake of glutarate were not affected. In addition, no signs of general toxic action could be observed. Specific basolateral binding affinity of PAH was reduced to 50% of control. Furthermore, incubation with OTA led to a decrease of PAH efflux across the apical membrane, although efflux across the basolateral membrane and the amount remaining in the cells increased as compared to control. By contrast to control cells, uptake of PAH in OTA-treated cells was not stimulated after preloading with glutarate. Our data show, that 1) long-term incubation with free OTA in the nanomolar range reduces the activity of the organic anion transporter, 2) without influencing general cell function. 3) OTA seems to act preferentially on organic anion transport, by affecting the exchange of organic anions and dicarboxylates. 4) Thereby, OTA reduces its own secretion. 5) The excretion of other xenobiotics and drugs may be also impaired, whereby OTA can exert an indirect toxic action.
赭曲霉毒素A（OTA）是一种广泛存在的霉菌毒素，具有肾毒性和致癌性。由于在体内长期暴露于OTA后观察到对氨基马尿酸（PAH）的净分泌减少，我们研究了OTA对源自近端小管的负鼠肾（OK）细胞的影响。当存在牛血清白蛋白（BSA）时，高达10^(-5)摩尔/升的OTA对PAH转运没有急性影响。相比之下，OK细胞孵育72小时导致PAH转运减少，经上皮分泌的半数最大抑制浓度为6×10^(-7)摩尔/升，PAH基底外侧摄取的半数最大抑制浓度为6×10^(-8)摩尔/升。用10^(-6)摩尔/升OTA孵育OK细胞72小时降低了PAH摄取的亲和力，并将最大分泌率降低至对照值的五分之一。氨基酸的顶端摄取和戊二酸的基底外侧摄取不受影响。此外，未观察到一般毒性作用的迹象。PAH的特异性基底外侧结合亲和力降低至对照的50%。此外，与OTA孵育导致PAH跨顶端膜的外排减少，尽管与对照相比，跨基底外侧膜的外排和细胞内剩余量增加。与对照细胞相比，用戊二酸预加载后OTA处理的细胞中PAH的摄取没有受到刺激。我们的数据表明，1）在纳摩尔范围内与游离OTA长期孵育会降低有机阴离子转运体的活性，2）而不影响一般细胞功能。3）OTA似乎优先作用于有机阴离子转运，通过影响有机阴离子和二羧酸盐的交换。4）由此，OTA减少了其自身的分泌。5）其他外源性物质和药物的排泄也可能受损，从而OTA可发挥间接毒性作用。
