Date of Award

1995

Document Type

Dissertation

Degree Name

Doctor of Biomedical and Veterinary Medical Sciences-Pathobiological Sciences (PVMPB)

Department

Veterinary Medical Sciences - Pathobiological Sciences

First Advisor

Jan L. VanSteenhouse

Abstract

The ability of acivicin (AT-125), probenecid, and aminooxyacetic acid (AOAA), to ameliorate 1-cyano-3,4-epithiobutane (CEB)-induced nephrotoxicity and karyomegaly was evaluated by histopathology and histomorphometry. Epithelial cell necrosis and karyomegaly were observed in the renal proximal tubules at 24 and 48 hours in all of the treated groups with the exception of AOAA pretreated rats at 24 hours. A predominant urinary metabolite of CEB was identified as the mercapturate, N-acetyl-S-(4-cyano-2-thio-1-butyl)-cysteine. Evidence of other urinary metabolites was also demonstrated. The influence of inhibitors on the GSH-enhancing effect of CEB was determined through measurement of tissue GSH levels and $\gamma$-glutamyl-cysteine synthetase (GCS) activity. Hepatic and renal GSH levels were significantly elevated in rats treated with CEB alone or CEB in addition to any of the inhibitors, with the exception of hepatic GSH at 24 hours in probenecid-pretreated rats. Renal GCS activity was significantly decreased at 24 hours in all of the treated groups with the exception of AOAA-pretreated rats. Activities of xenobiotic metabolizing enzymes were evaluated. No significant alterations were observed in renal or hepatic cytochrome P-450, ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-depentylase (PROD), and epoxide hydrolase (EH) activities. Renal and hepatic ethoxycoumarin O-deethylase (ECOD) and glutathione S-transferase (GST) activities, however, were significantly decreased in rats administered CEB. These results indicate a protective effect of AOAA against CEB-induced nephrotoxicity at 24 hours. AOAA inhibits the formation of a reactive thiol suggesting that such a metabolite may be responsible for CEB-induced nephrotoxicity. The reactive thiol also appears to inhibit renal GCS activity. The slight but statistically significant decrease in ECOD and GST are of questionable biological significance. However, diminished ECOD activity may be associated with the anticarcinogenic potential attributed to cruciferous vegetables. Identification of the urinary mercapturate represents detection of a unique compound and provides further evidence of the importance of GSH conjugation in CEB metabolism.

Pages

266

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