The mechanism of pentachlorobutadienyl-glutathione nephrotoxicity studied with isolated rat renal epithelial cells |
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| Authors: | T W Jones A Wallin H Thor R G Gerdes K Ormstad S Orrenius |
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| Institution: | 1. Department of Chemical Sciences, University of Naples “Federico II”, Naples, Italy;2. CSGI – Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase, Florence, Italy;3. Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples “Federico II”, 80134, Naples, Italy;4. Department of Medical, Oral and Biotechnological Sciences and CeSI-MeT, University of Chieti “G. d''Annunzio”, Via dei Vestini 31, 66100 Chieti, Italy;5. Institute of Molecular Biology and Pathology, CNR, Piazzale Aldo Moro 5, 00185 Rome, Italy;1. Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples “Federico II”, 80134 Naples, Italy;2. Analytical Chemistry for the Environment and CeSMA (Advanced Metrologic Service Center), University of Naples “Federico II”, Corso Nicolangelo Protopisani, 80146 Naples, Italy;3. Institute of Crystallography (IC), National Research Council, 70125, Bari, Italy;1. Department of Biology, Portland State University, P.O. Box 751, Portland, OR 97207, United States of America;2. Department of Biology, Saint Louis University, 1 N. Grand Blvd., St. Louis, MO 63103, United States of America;3. School of Life Sciences, University of Nevada, Las Vegas, 4505 S. Maryland Pkwy., Las Vegas, NV 89154, United States of America;4. Department of Animal Science, University of California, One Shields Ave., Davis, CA 95616, United States of America;5. Department of Psychological and Brain Sciences, Villanova University, 800 E. Lancaster Ave., Villanova, PA 19085, United States of America |
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| Abstract: | Isolated renal epithelial cells were used to study the mechanism of toxicity of pentachlorobutadienyl-glutathione (PCBG), a nephrotoxic glutathione conjugate of hexachlorobutadiene. The cytotoxicity of PCBG displayed a very steep dose-response relationship; at 10 microM PCBG no toxicity was observed whereas 25, 50, and 100 microM PCBG all resulted in a similar degree of toxicity. In all cases, loss of cell viability was observed only after a 30-min lag period and reached a plateau of 50 to 60% nonviable cells between 90 and 100 min. Toxic doses of PCBG also resulted in the depletion of cellular thiols. Blocking PCBG metabolism by inhibition of gamma-glutamyl transpeptidase 1-gamma-L-glutamyl-2-(2-carboxyphenyl)hydrazine (anthglutin), 2 mM] or renal cysteine conjugate beta-lyase (aminooxyacetic acid, 0.5 mM) resulted in complete protection against PCBG-induced cell damage. Exposure of isolated renal epithelial cells to 100 microM PCBG resulted in the rapid formation of plasma membrane blebs which appeared to be associated with a loss of Ca2+ from the mitochondrial compartment and an elevation of cytosolic Ca2+ concentration as measured by Quin-2. PCBG treatment also resulted in the inhibition of cell respiration and a marked depletion of cellular ATP content, indicating additional mitochondrial effects of the toxin. Our results support a role for renal cysteine conjugate beta-lyase in the metabolic activation of PCBG and suggest that PCBG-induced renal cell injury may be the result of selective effects on mitochondrial function. |
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