Reabsorption of the nephrotoxin ochratoxin A along the rat nephron in vivo.
Ochratoxin A (OTA) is a widespread nephrotoxin excreted to a substantial degree via the kidney. We investigated whether [3H]OTA is reabsorbed from the tubular lumen along the nephron and thus recycles within the kidney. Superficial early proximal and early distal tubules of male Wistar rats were micropunctured in situ. Microinfusion of OTA into superficial nephrons showed that it was reabsorbed in proximal as well as distal parts of the nephron. Reabsorption during early distal microinfusion was not saturable in the range of 0 to 5.10(-4) mol/liter and accounted for 20% of OTA infused. Reabsorption during early proximal microinfusion was partially saturable and reached values up to 70% of OTA infused. The apparent K(m) for OTA reabsorption was 236.10(-5) mol/liter and maximum transport rate 970 fmol/min/nephron. OTA reabsorption was pH dependent and decreased from 70 to 40% during proximal infusion and from 20 to 10% during distal infusion when pH increased from 6.0 to 7.4. The dipeptides carnosine and glyclysarcosine reduced OTA reabsorption significantly. L-Phenylalanine showed no significant inhibitory action. From our results we conclude: 1) there is substantial reabsorption of OTA along the nephron; 2) one-third of reabsorption takes place in the distal tubule and/or the collecting duct, two-thirds in the proximal tubule; 3) "distal" reabsorption can be explained at least in part by nonionic diffusion, because it was not saturable but pH dependent; 4) "proximal" reabsorption was in part mediated by the H(+)-dipeptide cotransporter; 5) reabsorption of filtered and secreted OTA delays its excretion and may lead to accumulation of the toxin in renal tissue and 6) inhibition of OTA reabsorption (e.g., by urine alkalinization) should help to accelerate OTA excretion and thus reduce its toxicity.
Zingerle
M
M
Physiologisches Institut, Universität Würzburg, Germany.
Silbernagl
S
S
Gekle
M
M
D000042:Absorption; D000818:Animals; D006863:Hydrogen-Ion Concentration; D008297:Male; D009183:Mycotoxins / Q000493:pharmacokinetics*; D009399:Nephrons / Q000378:metabolism*; D009793:Ochratoxins / Q000493:pharmacokinetics*; D010649:Phenylalanine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D009183:Mycotoxins; D009793:Ochratoxins; C025589:ochratoxin A; D010649:Phenylalanine