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Attenuation of 1,2,3‐trichloro‐4‐nitrobenzene nephrotoxicity by antioxidants and inhibitors of biotransformation
Author(s) -
Racine Christopher,
Ferguson Travis,
Preston Deborah,
Anestis Dianne,
Rankin Gary
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.889.9
Subject(s) - chemistry , nephrotoxicity , biotransformation , hepatoprotection , pharmacology , glutathione , antioxidant , metyrapone , biochemistry , enzyme , medicine , toxicity , organic chemistry
Chloronitrobenzenes (CNBs) are chemical intermediates used to manufacture a wide variety of compounds. CNBs are also nephrotoxicants in a rat renal cortical slice model. The purpose of this study was to explore the effects of antioxidants and inhibitors of renal biotransformation systems on 1,2,3‐trichloro‐4‐ nitrobenzene's (1,2,3‐TC4NB) nephrotoxic potential using isolated renal cortical cells (IRCC) from male Fischer 344 rats. Nephrotoxic potential was determined by incubating 1, 2, 3 – TC4NB (0 or 1 mM) with the IRCC (4 × 10 6 cells/ml) for 60 minutes and measuring lactate dehydrogenase (LDH) release. In some experiments, the cells were pretreated with an antioxidant [glutathione (1.0mM), α‐tocopherol (1.0 mM), N‐acetyl‐L‐cysteine (2.0 mM) or ascorbate (2.0 mM)], a cytochrome P450 inhibitor [piperonyl butoxide, isoniazid or metyrapone (1.0 mM)], a FMO inhibitor [N‐octylamine (0.2 mM) or methimazole (1.0 mM)], a peroxidase inhibitor [mercaptosuccinate (0.1 mM)] or a cyclooxygenase inhibitor [indomethacin (1.0 mM)]. 1,2,3‐TC4NB nephrotoxicity was reduced by all antioxidants, N‐octylamine, metyrapone and mercaptosuccinate. These results suggest that free radicals play a role in 1,2,3‐TC4NB nephrotoxicity and may result from multiple biotransformation pathways/intermediates. (Supported in part by NIH Grant 5P20RR016477 to the West Virginia IDeA Network for Biomedical Research Excellence)