Biotransformation and nephrotoxicity of ochratoxin B in rats.
Ochratoxin B (OTB), a secondary metabolite of Aspergillus ochraceus, is the nonchlorinated analogue of the mycotoxin ochratoxin A (OTA), which is one of the most potent renal carcinogens in rodents. Despite the closely related structure, OTB is considered to be of much lower toxicity. OTA is poorly metabolized and slowly eliminated, and this may play an important role in OTA toxicity, carcinogenicity, and organ specificity. Since little is known regarding biotransformation and renal toxicity of OTB, the aim of this study was to investigate biotransformation of OTB in rats and to characterize the nephrotoxicity and cytotoxicity of OTB. Male F344 rats were administered either a single dose of OTB (10 mg/kg bw) or repeated doses (2 mg/kg bw, 5 days/week for 2 weeks) and euthanized 72 h after the last dosing. In proximal tubule cells of animals treated with a single high dose of OTB, a slight increase in mitotic figures was observed, but no treatment-related changes were evident in clinical chemistry, in renal function, and histopathology after repeated administration. Excretion of OTB and metabolites in urine and feces was analyzed using both HPLC with fluorescence detection and LC-MS/MS. Ochratoxin beta, which results from cleavage of the peptide bond, was the major metabolite excreted in urine in addition to small amounts of 4-hydroxy-OTB. In total, 19% of the administered dose was recovered as OTB and ochratoxin beta in urine and feces within 72 h after a single dose. In contrast to OTA, no tissue-specific retention of OTB was evident after single and repeated administration. In LLC-PK1 cells, a renal cell culture system that retains much of the specific features of the proximal tubule, only minor differences in the extent of cytotoxicity of OTA and OTB were observed. At low concentrations (< 25 microM), treatment with OTA was slightly more toxic, whereas reduction in cell viability was similar at concentrations up to 100 microM. In summary, these data suggest that OTA and OTB have a similar potential to induce cytotoxicity in vitro, but large differences in their potential to induce nephrotoxicity in rodents. OTB is more extensively metabolized and more rapidly eliminated than OTA. The lack of specific retention of OTB in the kidneys and the differences in toxicokinetics may therefore provide an explanation for the lower toxicity of OTB.
Mally
Angela
A
Institut für Toxikologie, Universität Würzburg, 97078 Würzburg, Germany.
Keim-Heusler
Heike
H
Amberg
Alexander
A
Kurz
Michael
M
Zepnik
Herbert
H
Mantle
Peter
P
Völkel
Wolfgang
W
Hard
Gordon C
GC
Dekant
Wolfgang
W
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009793:Ochratoxins / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013552:Swine; D014018:Tissue Distribution
D002273:Carcinogens; D009793:Ochratoxins; C025589:ochratoxin A; C045354:ochratoxin B