Role of mitochondrial dysfunction in S-(1,2-dichlorovinyl)-L-cysteine-induced apoptosis

Yan Chen, Jiyang Cai, M. W. Anders, James L. Stevens, Dean P. Jones

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The nephrotoxicity of trichloroethylene and dichloroacetylene has previously been linked to mitochondrial dysfunction induced by the metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC). In this study, we examined whether key biochemical steps associated with mitochondria occur in DCVC-induced apoptosis in cultured porcine proximal tubular LLC-PK1 cells. DCVC caused a decrease in mitochondrial membrane potential (mtΔΨ) beginning at 4 h and a release of cytochrome c into the cytoplasm at 6 h. Caspase-3-like activity was detected at 6 h and extensive DNA fragmentation was observed at 8 h. Decreases in cellular ATP were not evident until 8 h and later, even though electron microscopy showed that the mitochondria were extensively swollen. Aminooxyacetic acid (AOAA), an inhibitor of cysteine-conjugate β-lyase, protected against mitochondrial changes and apoptosis. Overexpression of the antiapoptotic Bcl-2 protein desensitized LLC-PK1 cells to DCVC-induced apoptosis. These results support the interpretation that mitochondrial release of cyt c and cyt c-dependent activation of caspase-3 could have a central role in nephrotoxicity due to haloalkene-derived cysteine S-conjugates.

Original languageEnglish (US)
Pages (from-to)172-180
Number of pages9
JournalToxicology and Applied Pharmacology
Volume170
Issue number3
DOIs
StatePublished - Feb 1 2001
Externally publishedYes

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Apoptosis
Mitochondria
LLC-PK1 Cells
Caspase 3
Cysteine
Aminooxyacetic Acid
Trichloroethylene
Lyases
Metabolites
Cytochromes c
Electron microscopy
Mitochondrial Membrane Potential
DNA Fragmentation
Adenosine Triphosphate
Chemical activation
Membranes
Electron Microscopy
Cytoplasm
Swine
S-(1,2-dichlorovinyl)cysteine

Keywords

  • Apoptosis
  • Bcl-2
  • Haloalkenes
  • Membrane potential
  • Mitochondria
  • Nephrotoxicity

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Role of mitochondrial dysfunction in S-(1,2-dichlorovinyl)-L-cysteine-induced apoptosis. / Chen, Yan; Cai, Jiyang; Anders, M. W.; Stevens, James L.; Jones, Dean P.

In: Toxicology and Applied Pharmacology, Vol. 170, No. 3, 01.02.2001, p. 172-180.

Research output: Contribution to journalArticle

Chen, Yan ; Cai, Jiyang ; Anders, M. W. ; Stevens, James L. ; Jones, Dean P. / Role of mitochondrial dysfunction in S-(1,2-dichlorovinyl)-L-cysteine-induced apoptosis. In: Toxicology and Applied Pharmacology. 2001 ; Vol. 170, No. 3. pp. 172-180.
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