Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism

Cooper, Arthur J. L.; Bruschi, Sam A.; Anders, M.W.

doi:10.1016/s0006-2952(02)01076-6

Cited by 51 publications

(53 citation statements)

References 122 publications

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“…They are also important scavengers of oxygen-derived free radicals. 30,31 In this study, the thiol content, which is well known to be depleted following the toxicity of many haloalkenes, 32,33 was measured as an indicator of HCBD-induced nephrotoxicity. HCBD caused significant SH depletion in the kidney homogenate samples while PSO pretreatment resulted in a significant improvement.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of pomegranate seed oil on hexachlorobutadiene-induced nephrotoxicity in rat kidneys

et al. 2010

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In this study, the effect of pomegranate seed oil (PSO) on HCBD-induced nephrotoxicity was investigated in adult male rats. Animals were divided into five groups. Group 1 was treated with corn oil (1 mL/kg, i.p.). Group 2 received a single dose of HCBD (50 mg/kg, i.p.). Groups 3-5 were treated with PSO (0.16, 0.32, and 0.64 mg/kg, i.p., respectively) 1 h before HCBD (50 mg/kg, i.p.) injection. A significant elevation of serum creatinine and urea (p < 0.001) levels as well as urine glucose and protein (p < 0.001) concentrations (as markers of acute renal failure) was observed 24 h after administration of HCBD as compared to control group. HCBD also caused a significant decrease in total thiol content (p < 0.001) and a significant increase in thiobarbituric acid reactive species (TBARS, as an index of lipid peroxidation) levels (p < 0.001) in kidney homogenate samples. PSO pretreatment resulted in a significant and dose-dependent decrease in serum creatinine (p < 0.001) and urea levels (p < 0.001) as well as urine glucose (p < 0.001) and protein concentrations (p < 0.001) when compared with HCBD treated alone. PSO also significantly reversed the HCBD-induced depletion in total thiol content (p < 0.001) and elevation in TBARS (p < 0.001) in kidney homogenate samples. The results of this study showed that PSO clearly attenuated HCBD-induced nephrotoxicity, but explanation and mechanism of this protection need further explorations.

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Section: Discussionmentioning

confidence: 99%

Protective effect of pomegranate seed oil on hexachlorobutadiene-induced nephrotoxicity in rat kidneys

et al. 2010

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“…DCVC was demonstrated to be a potent cytotoxicant in freshly isolated rat PT (rPT) cells [9] and in LLC-PK1 cells [10], with production of mitochondrial dysfunction as an early effect. Similar studies in isolated mitochondria from rat kidneys showed DCVC to be a potent inhibitor of respiration and several dehydrogenases [11][12][13][14][15][16][17]. Changes in mitochondrial Ca 2+ ion homeostasis also appear to be a key step in DCVC-induced renal toxicity [13,[18][19][20].…”

Section: Introductionmentioning

confidence: 92%

Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells

Papanayotou

Putt

et al. 2008

Biochemical Pharmacology

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The nephrotoxic metabolite of the environmental contaminant trichloroethylene, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), is known to elicit cytotoxicity in rat and human proximal tubular (rPT and hPT, respectively) cells that involves inhibition of mitochondrial function. DCVC produces a range of cytotoxic and compensatory responses in hPT cells, depending on dose and exposure time, including necrosis, apoptosis, repair, and enhanced cell proliferation. The present study tested the hypothesis that induction of mitochondrial dysfunction is an obligatory step in the cytotoxicity caused by DCVC in primary cultures of hPT cells. DCVC-induced necrosis was primarily a highconcentration (≥ 50 μM) and lat (≥ 24 hr) response whereas apoptosis and increased proliferation occurred at relatively low concentrations (< 50 μM) and early time points (≤ 24 hr). Decreases in cellular DNA content, indicative of cell loss, were observed at DCVC concentrations as low as 1 μM. Involvement of mitochondrial dysfunction in DCVC-induced cytotoxicity was supported by showing that DCVC caused modest depletion of cellular ATP, inhibition of respiration, and activation of caspase-3/7. Cyclosporin A protected cells against DCVC-induced apoptosis and both cyclosporin A and ruthenium red protected cells against DCVC-induced loss of mitochondrial membrane potential. DCVC caused little or no activation of caspase-8 and did not significantly induce expression of Fas receptor, consistent with apoptosis occurring only by the mitochondrial pathway. These results support the conclusion that mitochondrial dysfunction is an early and obligatory step in DCVC-induced cytotoxicity in hPT cells.

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“…KGDHC activity is decreased in the kidneys of TFEC-treated rats (58,59) and in TFEC-treated PC12 cells (36). It was proposed that the susceptibility of KGDHC to inactivation by TFEC and to its thioacylation in rats treated with TFEC is due to close juxtapositioning of mitAspAT to KGDHC and to toxicant targeting of a reactive sulfurcontaining fragment from mitAspAT to KGDHC (24,25,59).…”

Section: Evidence That Mitaspat Is a Major Cysteine S-conjugate β-Lyamentioning

confidence: 99%

“…The S 3 regions of the kidney proximal tubules are especially susceptible to the effects of toxic cysteine Sconjugates (72). Mitochondria are the prime targets of toxic halogenated cysteine Sconjugates leading to cell death in kidney cells (24,25).Toxicity induced by cisplatin is similar to that induced by halogenated alkenes. In the kidney, the proximal tubules are targeted by cisplatin and mitochondria are especially vulnerable (73).…”

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confidence: 99%

Cisplatin-Induced Toxicity Is Associated with Platinum Deposition in Mouse Kidney Mitochondria in Vivo and with Selective Inactivation of the α-Ketoglutarate Dehydrogenase Complex in LLC-PK₁ Cells

et al. 2006

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The anti-cancer drug cisplatin is nephrotoxic and neurotoxic. Previous data support the hypothesis that cisplatin is bioactivated to a nephrotoxicant. The final step in the proposed bioactivation is the formation of a platinum-cysteine S-conjugate followed by a pyridoxal 5'-phosphate (PLP)-dependent cysteine S-conjugate β-lyase reaction. This reaction would generate pyruvate, ammonium and a highly reactive platinum (Pt)-thiol compound in vivo that would bind to proteins. In the present work, the cellular location and identity of the PLP-dependent cysteine S-conjugate β-lyase was investigated. Pt was shown to bind to proteins in kidneys of cisplatin-treated mice.The concentration of Pt-bound proteins was higher in the mitochondrial fraction than in the cytosolic fraction. Treatment of the mice with aminooxyacetic acid (AOAA, a PLP-enzyme inhibitor), which had previously been shown to block the nephrotoxicity of cisplatin, decreased the binding of Pt to mitochondrial proteins, but had no effect on the amount of Pt bound to proteins in cytAspAT, cytosolic aspartate aminotransferase; DCVC, S-(1,2-dichlorovinyl)-L-cysteine; DMEM, Dulbecco's Modified Eagle's Medium; GFAAS, graphite furnace atomic absorption spectrometry; FBS, fetal bovine serum; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GDH, glutamate dehydrogenase; GGT, γ-glutamyl transpeptidase; GTK, glutamine transaminase K; HBSS, Hanks' balanced salt solution; KGDHC, α-ketoglutarate dehydrogenase complex; LDH, lactate dehydrogenase; MDH, malate dehydrogenase; mitAspAT, mitochondrial aspartate aminotransferase; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; pmitAspAT, precursor of mitochondrial aspartate aminotransferase; PLP, pyridoxal 5'-phosphate; PMP, pyridoxamine 5'-phosphate; SD, standard deviation; SEM, standard error of the mean; TFEC, S-(1,1,2,2-tetrafluoroethyl)-L-cysteine. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2014 August 14. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the cytosolic fraction. These data indicate that a mitochondrial enzyme catalyzes the PLPdependent cysteine S-conjugate β-lyase reaction. PLP-dependent mitochondrial aspartate aminotransferase (mitAspAT) is a mitochondrial enzyme that catalyzes β-elimination reactions with cysteine S-conjugates of halogenated alkenes. We reasoned that the enzyme might also catalyze a β-lyase reaction with the cisplatin-cysteine S-conjugate. In the present study mitAspAT was stably overexpressed in LLC-PK 1 cells. Cisplatin was significantly more toxic in confluent monolayers of LLC-PK 1 cells that overexpressed mitAspAT when compared to control cells containing vector alone. AOAA completely blocked the cisplatin toxicity in confluent mitAspATtransfected cells. The Pt-thiol compound could rapidly bind proteins and inactivate enzymes in close proximity to the PLP-dependent cysteine S-conjugate β-lyase. Treatment with 50-or 100 µM cisplatin for 3 h, followed by removal of cisplatin from the medium ...

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Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism

Cited by 51 publications

References 122 publications

Protective effect of pomegranate seed oil on hexachlorobutadiene-induced nephrotoxicity in rat kidneys

Protective effect of pomegranate seed oil on hexachlorobutadiene-induced nephrotoxicity in rat kidneys

Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells

Cisplatin-Induced Toxicity Is Associated with Platinum Deposition in Mouse Kidney Mitochondria in Vivo and with Selective Inactivation of the α-Ketoglutarate Dehydrogenase Complex in LLC-PK₁ Cells

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Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism

Cited by 51 publications

References 122 publications

Protective effect of pomegranate seed oil on hexachlorobutadiene-induced nephrotoxicity in rat kidneys

Protective effect of pomegranate seed oil on hexachlorobutadiene-induced nephrotoxicity in rat kidneys

Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells

Cisplatin-Induced Toxicity Is Associated with Platinum Deposition in Mouse Kidney Mitochondria in Vivo and with Selective Inactivation of the α-Ketoglutarate Dehydrogenase Complex in LLC-PK1 Cells

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Cisplatin-Induced Toxicity Is Associated with Platinum Deposition in Mouse Kidney Mitochondria in Vivo and with Selective Inactivation of the α-Ketoglutarate Dehydrogenase Complex in LLC-PK₁ Cells