Stein, Aron Farre (1983-04). Toxic and biologic effects of ochratoxin A in the partially nephrectomized rat : a dissertation. Doctoral Dissertation.
Thesis
ABSTRACT: The effects of ochratoxin A (OA), a nephrotoxic mycotoxin, were investigated in partially nephrectomized (PN) rats. Daily administration of low levels of OA produced decreases in urine osmolality, and body weight. OA treated rats cleared inulin, creatinine and PAH at rates significantly lower than non-treated controls. Histopathological findings indicated a considerable increase in renal tubular necrosis and subcellular damage in PN animals versus controls. A reverse phase HPLC analysis was developed for the quantitation and confirmation of OA in biological tissues and fluids. OA derviatized to an O-methyl, methyl ester (OA-Me2) with diazomethane gave a retention time of 309 sec with a detection of 3 ng. Recovery of OA as OA-Me2 from rat kidney homogenate and plasma was quantitative. The elimination, distribution, and metabolism of OA was studied in SO and PN rats. Peak OA serum concentrations occurred at 1.0 and 2.0 hr in PN and SO rats. PN rats had no detectable levels of ochratoxin alpha in urine samples at 24 hr. The increase in the distribution half-life in the PN rats may be responsible for the greater susceptibility to the nephrotoxic effects of OA. Renal clearance studies on the handling of acutely administered [3H] were performed on pentobarbitol-anesthetized rats. SO and PN rats cleared OA at 0.109 and 0.078 ml/min, respectively. The effects of probenecid was investigated in rats to determine the role of secretion of OA. The clearance rates were significantly reduced by pretreatment with probenecid. Renal function in rats given 5 daily consecutive doses of 2.0 mg/kg of OA and probenecid or OA alone was investigated to observe any protective characteristics of probenecid. OA-probenecid treated animals exhibited decreases in urine osmolality, Na and K concentrations, and body weight when compared with the rats given only OA. Probenecid had no effect on liver and kidney concentrations of OA, yet histopathology revealed less extensive focal necrosis in kidneys from the combination OA-probenecid group than the OA controls. The mechanism of nephrotoxicity may be of a multifactorial nature and related to the exposure of OA in renal proximal tubular cells via transport or reabsorption processes.
