Protection from 1-cyano-3,4-epithiobutane nephrotoxicity by aminooxyacetic acid and effect on xenobiotic-metabolizing enzymes in male Fischer 344 rats.
1-Cyano-3,4-epithiobutane (CEB), a naturally occurring nitrile derived from cruciferous plants, causes nephrotoxicity and increased renal glutathione (GSH) concentration in male F-344 rats. This CEB-induced nephrotoxicity is dependent on GSH conjugation and bioactivation. The objectives of the present study were to investigate the effect of CEB on several xenobiotic-metabolizing enzymes and to evaluate the effect of modulators of GSH transport and metabolism on CEB-induced nephrotoxicity and GSH concentration. Animals received 125 mg kg-1 CEB alone or following pretreatment with one of three selective inhibitors of GSH metabolism: acivicin, probenecid or aminooxyacetic acid. There were no significant alterations in epoxide hydrolase (EH), P-450, ethoxyresorufin O-deethylase (EROD) or pentoxyresorufin O-depentylase (PROD) enzyme activity, but renal glutamyl cysteine synthetase (GCS) activity was decreased at 12 and 24 h, as was renal glutathione S-transferase 4 h after CEB administration. Renal ECOD activity was also diminished at 24 h and at 12 and 24 h in liver. Aminooxyacetic acid (AOAA) abrogated the nephrotoxicity, the renal GSH-enhancing effect, and decreased GCS of CEB alone. These findings provide further evidence for the importance of GSH conjugation as a significant pathway in CEB metabolism and the role of a reactive thiol in nephrotoxicity and altered renal GSH.
VanSteenhouse
J L
JL
Department of Veterinary Pathology, School of Veterinary Medicine, Louisiana State University, Baton Rouge 70803, USA. vansteen@vetmed.dsu.edu
Prescott
J S
JS
Swenson
D H
DH
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009570:Nitriles / Q000633:toxicity*; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D009570:Nitriles; D000625:Aminooxyacetic Acid; C062529:1-cyano-3,4-epithiobutane; D003577:Cytochrome P-450 Enzyme System; D015660:7-Alkoxycoumarin O-Dealkylase; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D004851:Epoxide Hydrolases; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; C006303:acivicin; D011339:Probenecid