Deborah Pope, C. Tyree, Christopher R Racine
Jul 26, 2016
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Proceedings of the West Virginia Academy of Science
Abstract
Chloronitrobenzenes are key chemical intermediates used in the manufacture of dyes, agricultural agents and industrial compounds. Although some data exists on the toxicity of mono- and dichloronitrobenzenes, there is a paucity of data on the toxicity profile of trichloronitrobenzenes (TCNBs). One of the target organs for mono- and dichloronitrobenzenes is the kidney. The purpose of this study was to examine the in vitro nephrotoxic potential of two TCNBs, 2,4,5-trichloronitrobenzene (2,4,5-TCNB) and 2,4,6- trichloronitrobenzene (2,4,6-TCNB), using freshly isolated rat renal cortical cells (IRCC), and to study potential mechanisms of bioactivation and toxicity. Briefly, IRCC were obtained from male Fischer 344 rats using a collagenase perfusion technique and incubated (~4 million cells/ml, 3 ml) with a TCNB (0.5 or 1.0 mM) or vehicle (dimethyl sulfoxide) for up to 90 min. In some experiments, cells were pretreated with an antioxidant (ascorbate, alpha-tocopherol, glutathione, N-acetyl-L-cysteine) or metabolizing enzyme inhibitor prior to a TCNB or vehicle treatment. Cytotoxicity was determined by measuring lactate dehydrogenase release. 2,4,6-TCNB induced cytotoxicity as early as 60 min and at 0.5 mM, while 2,4,5-TCNB did not induce cytotoxicity until 90 min at 1.0 mM. Antioxidant pretreatments were effective in reducing the toxicity induced by both TCNBS but were more effective against 2,4,5-TCNB. Cyclooxygenase inhibition reduced 2,4,6-TCNB, but not 2,4,5-TCNB, cytotoxicity, while inhibition of cytochrome P450, flavin monooxygenase and peroxidase activity were not protective. These results suggest 2,4,6-TCNB is more nephrotoxic than 2,4,5-TCNB and that free radicals contribute to TCNB nephrotoxicity in vitro.Supported in part by NIH grant P20GM103434.