Abstract:
:Diclofenac, a widely used nonsteroidal anti-inflammatory drug, has been associated with rare but severe cases of clinical hepatotoxicity. Diclofenac causes concentration-dependent cell death in human hepatocytes (after 24-48 h) by mitochondrial permeabilization via poorly defined mechanisms. To explore whether the cyclophilin D (CyD)-dependent mitochondrial permeability transition (mPT) and/or the mitochondrial outer membrane permeabilization (MOMP) was primarily involved in mediating cell death, we exposed immortalized human hepatocytes (HC-04) to apoptogenic concentrations of diclofenac (>500 microM) in the presence or absence of inhibitors of upstream mediators. The CyD inhibitor, cyclosporin A (CsA, 2 microM) fully inhibited diclofenac-induced cell injury, suggesting that mPT was involved. However, CyD gene silencing using siRNA left the cells susceptible to diclofenac toxicity, and CsA still protected the CyD-negative cells from lethal injury. Diclofenac induced early (9 h) activation of Bax and Bak and caused mitochondrial translocation of Bax, indicating that MOMP was involved in cell death. Inhibition of Bax protein expression by using siRNA significantly protected HC-04 from diclofenac-induced cell injury. Diclofenac also induced early Bid activation (tBid formation, 6 h), which is an upstream mechanism that initiates Bax activation and mitochondrial translocation. Bid activation was sensitive to the Ca2+ chelator, BAPTA. In conclusion, we found that Bax/Bak-mediated MOMP is a key mechanism of diclofenac-induced lethal cell injury in human hepatocytes, and that CsA can prevent MOMP through inhibition of Bax activation. These data support our concept that the Ca2+-Bid-Bax-MOMP axis is a critical pathway in diclofenac (metabolite)-induced hepatocyte injury.
journal_name
Toxicol Appl Pharmacoljournal_title
Toxicology and applied pharmacologyauthors
Siu WP,Pun PB,Latchoumycandane C,Boelsterli UAdoi
10.1016/j.taap.2007.11.030subject
Has Abstractpub_date
2008-03-15 00:00:00pages
451-61issue
3eissn
0041-008Xissn
1096-0333pii
S0041-008X(07)00523-6journal_volume
227pub_type
杂志文章abstract::As a part of the serotoninergic dysfunction implicated in neurobiology of depression, evidence has focused on serotonin (5-HT) receptors downstream signaling intermediates including glycogen synthase kinase-3β (GSK-3β), cAMP response element binding protein (CREB) and brain derived neurotrophic factor (BDNF). Our team...
journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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doi:10.1016/j.taap.2010.10.002
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章,评审
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journal_title:Toxicology and applied pharmacology
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pub_type: 杂志文章
doi:10.1016/j.taap.2005.03.005
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journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
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更新日期:2010-06-15 00:00:00
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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journal_title:Toxicology and applied pharmacology
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abstract::Arsenic is an effective therapeutic agent for the treatment of patients with refractory or relapsed acute promyelocytic leukemia. The use of arsenic for treating solid tumors, particularly in combination with other chemotherapeutic agents, has been extensively studied. Here, we report that arsenite-resistant human lun...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
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更新日期:2006-08-01 00:00:00
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journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(90)90284-2
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journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.2001.9214
更新日期:2001-08-01 00:00:00
abstract::This study assessed the role of aryl hydrocarbon receptor (AHR) affinity, and cytochrome P4501A (CYP1A) protein and activity in polyaromatic hydrocarbon (PAH)-induced oxidative stress. In the 1-100nM concentration range benzo[a]pyrene (BaP) but not benzo[e]pyrene (BeP) competitively displaced 2nM [(3)H]2, 3, 7, 8-tetr...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2011.04.015
更新日期:2011-07-01 00:00:00