Exposure to ochratoxin A impairs organic anion transport in proximal-tubule-derived opossum kidney cells.
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.
Sauvant
C
C
Physiologisches Institut, Universität Würzburg, Würzburg, Germany.
Silbernagl
S
S
Gekle
M
M
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D009183:Mycotoxins / Q000633:toxicity*; D009793:Ochratoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D009893:Opossums; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
D009183:Mycotoxins; D009793:Ochratoxins; C025589:ochratoxin A; D010130:p-Aminohippuric Acid