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  • 1
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 161 (1994), S. 293-302 
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Addition of the nephrotoxic cysteine conjugate, S-(1, 2-dichlorovinyl)-L-cysteine (DCVC), to the LLC-PK1 line of renal epithelial cells leads to covalent binding of reactive intermediates followed by thiol depletion, lipid peroxidation, and cell death (Chen et al., 1990, J. Biol. Chem., 265:21603-21611.) The present study was designed to determine if increased intracellular free calcium might play a role in this pathway of DCVC-induced toxicity by comparing the temporal relationships among increased intracellular free calcium, lipid peroxidation, and cytotoxicity. Intracellular free calcium increased 1 hr after DCVC treatment, long before LDH release occurred. The elevation of intracellular free calcium and cytotoxicity was prevented by inhibiting DCVC metabolism with AOA. The cell-permeable chelators, Quin-2AM and EGTA-AM, prevented the toxicity. Pretreatment of cells with a nontoxic concentration of ionomycin increased intracellular free calcium and potentiated DCVC-induced LDH release. However, the antioxidant, DPPD, which blocks lipid peroxidation and toxicity, did not affect the increase in intracellular free calcium, whereas buffering intracellular calcium with Quin-2AM or EGTA-AM blocked both lipid peroxidation and toxicity without preventing the depletion of nonprotein sulfhydryls by DCVC. Ruthenium red, an inhibitor of mitochondrial calcium uptake, also blocked cell death. We hypothesize that covalent binding of the reactive fragment from DCVC metabolism leads to deregulation of intracellular calcium homeostasis and elevation of intracellular free calcium. Increased intracellular free calcium may in turn be coupled to mitochondrial damage and the accumulation of endogenous oxidants which cause lipid peroxidation and cell death. © 1994 Wiley-Liss, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Nephrotoxic and mutagenic cysteine conjugates (NCC) are activated by the enzyme cysteine conjugate, β-lyase, to reactive acylating species which bind covalently to cellular macromolecules. We now show that an early event after treatment of LLC-PK1 cells with NCC is the induction of mRNA for both c-fos and c-myc. Treatment with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) induced c-fos (53-fold) and c-myc mRNA (20-fold) and increased transcription about 3-fold for both genes. Covalent binding was required for induction of both mRNAs. Dithiothreitol partially prevented induction of both c-fos and c-myc RNA. Buffering the DCVC-induced increase in cytosolic free calcium had no effect on c-fos mRNA but partially blocked c-myc mRNA induction. Cycloheximide blocked the induction of c-myc mRNA in the absence of an effect on c-fos induction. The data suggest that the increase in c-fos mRNA is a primary response to DCVC toxicity and occurs without a requirement for protein synthesis or an increase in intracellular free calcium. In contrast, c-myc induction requires protein synthesis, suggesting that the presence of another primary response factor may regulate induction either transcriptionally or posttranscriptionally. The data suggest that different signalling pathways regulate induction of c-fos and c-myc mRNA in response to stress caused by reactive acylating species. © 1994 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    Library Location Call Number Volume/Issue/Year Availability
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