The Endoplasmic Reticulum in Xenobiotic Toxicity

Cribb, Alastair E.; Peyrou, Mathieu; Muruganandan, Shanmugam; Schneider, Laetitia

doi:10.1080/03602530500205135

Cited by 141 publications

(78 citation statements)

References 221 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Conditioning with thapsigargin or calcium ionophores prevented oxidative stress-dependent cell death in renal epithelial cells, through induction of ER stress proteins [47]. There are few studies on the ability of ER stress protein induction to provide cytoprotection in the liver [46]. After induction of ER stress, no protection against agents associated with oxidative stress (menadione, tert-butyl hydroperoxide) was observed in hepatoma cells (HepG2 and H4IIE), suggesting that protection afforded by the ER stress response may be cell type-specific [48].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of intracellular calcium and phospholipase A2 in arachidonic acid-induced toxicity in liver cells overexpressing CYP2E1

Andrés¹,

Cederbaum²

2007

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

Liver cells (HepG2 and primary hepatocytes) overexpressing CYP2E1 and exposed to arachidonic acid (AA) were previously shown to lose viability together with enhanced lipid peroxidation. These events were blocked in cells pre-incubated with antioxidants (α -tocopherol, glutathione ethyl ester), or in HepG2 cells not expressing CYP2E1. The goal of the current study was to evaluate the role of calcium and calcium-activated hydrolases in these CYP2E1-AA interactions. CYP2E1-expressing HepG2 cells treated with AA showed an early increase in cytosolic calcium and partial depletion of ionomycin-sensitive calcium stores. These changes in calcium were blocked by α -tocopherol. AA activated phospholipase A2 (PLA2) in CYP2E1-expressing liver cells, and this was inhibited by PLA2 inhibitors or α -tocopherol. PLA2 inhibitors prevented the cell death caused by AA, without affecting CYP2E1 activity or lipid peroxidation. AA toxicity and PLA2 activation were inhibited in calcium-depleted cells, but not by removal of extracellular calcium alone. Removal of extracellular calcium inhibited the early increase in cytosolic calcium caused by AA. CYP2E1 overexpressing HepG2 cells exposed to AA showed a decrease in mitochondrial membrane potential, which was prevented by the PLA2 inhibitors. These results suggest that AA-induced toxicity to CYPE1-expressing cells: (i) is associated with release of Ca 2+ from intracellular stores that depends mainly on oxidative membrane damage; (ii) is associated with activation of PLA2 that depends on intracellular calcium and lipid peroxidation; iii) does not depend on increased influx of extracellular calcium, and iv) depends on the effect of converging events (lipid peroxidation, intracellular calcium, activation of PLA2) on mitochondria to induce bioenergetic failure and necrosis. These interactions may play a role in alcohol liver toxicity, which requires polyunsaturated fatty acids, and involves induction of CYP2E1.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Thapsigargin and calcium ionophores are classical inducers of the ER stress response through ER calcium depletion [46]. Conditioning with thapsigargin or calcium ionophores prevented oxidative stress-dependent cell death in renal epithelial cells, through induction of ER stress proteins [47].…”

Section: Discussionmentioning

confidence: 99%

Role of intracellular calcium and phospholipase A2 in arachidonic acid-induced toxicity in liver cells overexpressing CYP2E1

Andrés¹,

Cederbaum²

2007

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

show abstract

“…ostasis (Braakman and Bulleid, 2011;Cribb et al, 2005;Fagone and Jackowski, 2009). The process of protein folding is executed by folding and oxidising enzymes, aided by chaperones and glycosylating enzymes that require high Ca 2+ levels typically present inside the ER lumen, as well as ATP and an oxidising environment (Braakman and Bulleid, 2011).…”

mentioning

confidence: 99%

The unfolded protein response at the crossroads of cellular life and death during endoplasmic reticulum stress

Jäger

Bertrand

Gorman

et al. 2012

Biology of the Cell

181

139

View full text Add to dashboard Cite

One of the early cellular responses to endoplasmic reticulum (ER) stress is the activation of the unfolded protein response (UPR). ER stress and the UPR are both implicated in numerous human diseases and pathologies. In spite of this, our knowledge of the molecular mechanisms that regulate cell fate following ER stress is limited. The UPR is initiated by three ER transmembrane receptors: PKR-like ER kinase (PERK), activating transcription factor (ATF) 6 and inositol-requiring enzyme 1 (IRE1). These proteins sense the accumulation of unfolded proteins and their activation triggers specific adaptive responses to resolve the stress. Intriguingly, the very same receptors can initiate signalling pathways that lead to apoptosis when the attempts to resolve the ER stress fail. In this review, we describe the known pro-apoptotic signalling pathways emanating from activated PERK, ATF6 and IRE1 and discuss how their signalling switches from an adaptive to a pro-apoptotic response. ER stress and unfolded protein responseThe endoplasmic reticulum (ER) is a threedimensional cellular network of extensive interlinked membranous tubules, sacs and flattened cisternae. It spans from the nuclear envelope to the secretory vesicles. The morphology and the extent of the ER network organisation very much depend on the predominant function(s) of any given cell type. The ER participates in a variety of cellular functions such as synthesis and sorting of secretory and membrane proteins, biosynthesis of phospholipids, cholesterol, steroids, degradation of glycogen, detoxification reactions and maintenance of intracellular calcium home-1 To whom correspondence should be addressed (email afshin.samali@nuigalway.ie).

show abstract

“…The A subunit of AB 5 subtilase is a serine protease that cleaves GRP78 at a single site, resulting in its selective inactivation, thereby triggering death in the target cells. PDIs participate in the correct protein folding of newly synthesized proteins through the maintenance of proper disulfide bridges (94)(95)(96)(97). GRP78 is among the genes that are significantly up-regulated in response to subtoxic doses of 4-HNE, a lipid peroxidation-derived R, -unsaturated aldehyde that covalently modifies proteins during oxidative stress (98).…”

Section: Discussionmentioning

confidence: 99%

Identification of the Protein Targets of the Reactive Metabolite of Teucrin A in Vivo in the Rat

Druckova

Mernaugh

Ham

et al. 2007

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Covalent modification of proteins is associated with the toxicity of many electrophiles, and the identification of relevant in vivo protein targets is a desirable but challenging goal. Here, we describe a strategy for the enrichment of adducted proteins utilizing single-chain fragment variable (ScFv) antibodies selected using phage-display technology. Teucrin A is a furan-containing diterpenoid found in the herb germander that is primarily responsible for the herb's hepatotoxicity in rodents and humans following metabolic activation by cytochrome P450 enzymes. Conjugates of the 1,4-enedial derivative of teucrin A, its presumed toxic metabolite, with lysine-and cysteine-containing peptides were synthesized and used to select ScFvs from a rodent phage-displayed library, which recognized the terpenoid moiety of the teucrin-derived adducts. Immunoaffinity isolation of adducted proteins from rat liver homogenates following administration of a toxic dose of teucrin A afforded a family of proteins that were identified by liquid chromatography/tandem mass spectrometry. Of the 46 proteins identified in this study, most were of mitochondrial and endoplasmic reticulum origin. Several cytosolic proteins were found, as well as four peroxisomal and two secreted proteins. Using Ingenuity Pathway Analysis software, two significant networks involving the target genes were identified that had major functions in gene expression, small molecule biochemistry, and cellular function and maintenance. These included proteins involved in lipid, amino acid, and drug metabolism. This study illustrates the utility of chemically synthesized biological conjugates of reactive intermediates and the potential of the phage display technology for the generation of affinity reagents for the isolation of adducted proteins.

show abstract

The Endoplasmic Reticulum in Xenobiotic Toxicity

Cited by 141 publications

References 221 publications

Role of intracellular calcium and phospholipase A2 in arachidonic acid-induced toxicity in liver cells overexpressing CYP2E1

Role of intracellular calcium and phospholipase A2 in arachidonic acid-induced toxicity in liver cells overexpressing CYP2E1

The unfolded protein response at the crossroads of cellular life and death during endoplasmic reticulum stress

Identification of the Protein Targets of the Reactive Metabolite of Teucrin A in Vivo in the Rat

Contact Info

Product

Resources

About