Toxicokinetics of the mycotoxin ochratoxin A in F 344 rats after oral administration

Abstract

Ochratoxin A (OTA), a mycotoxin produced by several fungi of Aspergillus and Penicillium species, is a nephrotoxin and a renal carcinogen in rodents. This study was performed to investigate the biotransformation and toxicokinetics of this important food contaminant. Male ( n = 18) and female ( n = 18) F344 rats were administered a single dose of OTA (0.5 mg/kg b.w.) in corn oil by gavage. Animals ( n = 3) were sacrificed 24, 48, 72, 96, 672, and 1,344 hours after OTA administration and concentrations of OTA and OTA-metabolites in urine, feces, blood, liver, and kidney were determined by HPLC with fluorescence detection and/or by LC-MS/MS. Recovery of unchanged OTA in urine amounted to 2.1% of dose in males and 5.2% in females within 96 h. In feces, only 5.5% respectively 1.5% of dose were recovered. The major metabolite detected was OTalpha; low concentrations of OTA-glucosides were also present in urine. The maximal blood levels of OTA were observed between 24 and 48 h after administration and were appromixately 4.6 μmol/l in males and 6.0 μmol/l in females. Elimination of OTA from blood followed first-order kinetics with a half-life of approximately 230 h. In liver of both male and female rats, OTA-concentrations were less than 12 pmol/g tissue, with a maximum at 24 h after administration. In contrast, OTA accumulated in the kidneys, reaching a concentration of 480 pmol/g tissue in males 24 h after OTA-administration. Generally, tissue concentrations in males were higher than in females. OTalpha was not detected in liver and kidney tissue of rats administered OTA, and the OTalpha concentrations in blood were low (10–15 nmol/l). The high concentrations of OTA in kidneys of male rats may, in part, explain the organ- and gender-specific toxicity of OTA.