Bax-mediated mitochondrial outer membrane permeabilization (MOMP), distinct from the mitochondrial permeability transition, is a key mechanism in diclofenac-induced hepatocyte injury: Multiple protective roles of cyclosporin A.


: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.


Toxicol Appl Pharmacol


Siu WP,Pun PB,Latchoumycandane C,Boelsterli UA




Has Abstract


2008-03-15 00:00:00














  • Monocrotaline pyrrole induces apoptosis in pulmonary artery endothelial cells.

    abstract::In the monocrotaline (MCT) model of pulmonary hypertension, the pulmonary vascular endothelium is the likely early target of the reactive metabolite monocrotaline pyrrole (MCTP). Incubation of cultured bovine pulmonary arterial endothelial cells (BPAEC) with MCTP results in covalent binding to DNA, cell cycle arrest, ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Thomas HC,Lamé MW,Dunston SK,Segall HJ,Wilson DW

    更新日期:1998-08-01 00:00:00

  • Arsenic induces platelet shape change through altering focal adhesion kinase-mediated actin dynamics, contributing to increased platelet reactivity.

    abstract::Arsenic, an environmental contaminant in drinking water worldwide is well-established to increase cardiovascular diseases (CVDs) in humans. Of these, thrombotic events represent a major adverse effect associated with arsenic exposure, for which an abundance of epidemiological evidence exists. Platelet aggregation cons...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Kim K,Shin EK,Chung JH,Lim KM

    更新日期:2020-03-15 00:00:00

  • The AH receptor and a novel gene determine acute toxic responses to TCDD: segregation of the resistant alleles to different rat lines.

    abstract::2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD),12 the most toxic congener of dioxins, exhibits wide sensitivity differences between a sensitive Long-Evans (L-E) rat and a resistant Han/Wistar (H/W) rat. The sensitivity is determined probably by two autosomal genes and it is highly end point dependent. The difference is mo...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Tuomisto JT,Viluksela M,Pohjanvirta R,Tuomisto J

    更新日期:1999-02-15 00:00:00

  • Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone.

    abstract::Statins are widely used to treat lipid disorders. These drugs are safe and well tolerated; however, in <1% of patients, myopathy and/or rhabdomyolysis can develop. To better understand the mechanism of statin-induced myopathy, we examined the ability of structurally distinct statins to induce apoptosis in an optimized...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Johnson TE,Zhang X,Bleicher KB,Dysart G,Loughlin AF,Schaefer WH,Umbenhauer DR

    更新日期:2004-11-01 00:00:00

  • Evidence that pyrrole formation is a pathogenetic step in gamma-diketone neuropathy.

    abstract::Previous studies from this laboratory have demonstrated that the addition of methyl groups at the 3 and 4 positions of the 2,5-hexanedione (2,5-HD) molecule results both in more rapid pyrrole formation and in enhanced neurotoxicity. In order to define more clearly the relationship between rates of pyrrole formation an...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Genter MB,Szakál-Quin G,Anderson CW,Anthony DC,Graham DG

    更新日期:1987-02-01 00:00:00

  • Effect of JP-8 jet fuel on molecular and histological parameters related to acute skin irritation.

    abstract::Organic chemicals such as jet fuels and solvents can cause skin irritation after dermal exposure. The molecular responses to these chemicals resulting in acute irritation are not understood well enough to establish safe exposure limits. Male F-344 rats were dermally exposed to JP-8 jet fuel for 1 h using Hill Top Cham...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Kabbur MB,Rogers JV,Gunasekar PG,Garrett CM,Geiss KT,Brinkley WW,McDougal JN

    更新日期:2001-08-15 00:00:00

  • Identification and characterization of naturally occurring inhibitors against UDP-glucuronosyltransferase 1A1 in Fructus Psoraleae (Bu-gu-zhi).

    abstract::As an edible traditional Chinese herb, Fructus psoraleae (FP) has been widely used in Asia for the treatment of vitiligo, bone fracture and osteoporosis. Several cases on markedly elevated bilirubin and acute liver injury following administration of FP and its related proprietary medicine have been reported, but the m...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Wang XX,Lv X,Li SY,Hou J,Ning J,Wang JY,Cao YF,Ge GB,Guo B,Yang L

    更新日期:2015-11-15 00:00:00

  • Calcitriol ameliorated autonomic dysfunction and hypertension by down-regulating inflammation and oxidative stress in the paraventricular nucleus of SHR.

    abstract::The hypothalamic paraventricular nucleus (PVN) plays crucial roles in central cardiovascular regulation. Increasing evidence in humans and rodents shows that vitamin D intake is important for achieving optimal cardiovascular function. The purpose of this study was to investigate whether calcitriol, an active form of v...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Xu ML,Yu XJ,Zhao JQ,Du Y,Xia WJ,Su Q,Du MM,Yang Q,Qi J,Li Y,Zhou SW,Zhu GQ,Li HB,Kang YM

    更新日期:2020-05-01 00:00:00

  • Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis.

    abstract::Tamoxifen is a widely used anti-estrogenic drug for chemotherapy and, more recently, for the chemoprevention of breast cancer. Despite the indisputable benefits of tamoxifen in preventing the occurrence and re-occurrence of breast cancer, the use of tamoxifen has been shown to induce non-alcoholic steatohepatitis, whi...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Pogribny IP,Bagnyukova TV,Tryndyak VP,Muskhelishvili L,Rodriguez-Juarez R,Kovalchuk O,Han T,Fuscoe JC,Ross SA,Beland FA

    更新日期:2007-11-15 00:00:00

  • Nasal cytochrome P450 2A: identification, regional localization, and metabolic activity toward hexamethylphosphoramide, a known nasal carcinogen.

    abstract::Two members of the cytochrome P450 2A subfamily, CYP2A10 and 2A11, are abundant nasal enzymes previously characterized in rabbit olfactory microsomes. Rabbit CYP2A is active toward a number of nasal toxicants, including the rat nasal procarcinogen hexamethylphosphoramide (HMPA). While P450s immunochemically related to...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Thornton-Manning JR,Nikula KJ,Hotchkiss JA,Avila KJ,Rohrbacher KD,Ding X,Dahl AR

    更新日期:1997-01-01 00:00:00

  • Effects of phospholipid surfactant on apoptosis induction by respirable quartz and kaolin in NR8383 rat pulmonary macrophages.

    abstract::Apoptosis was measured in rat alveolar macrophage NR8383 cells challenged in vitro with respirable quartz or kaolin dust and with the dusts pretreated with dipalmitoyl phosphatidylcholine (DPPC) to model conditioning of respired dusts by interaction with a primary phospholipid component of pulmonary surfactant. Quartz...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Gao N,Keane MJ,Ong T,Ye J,Miller WE,Wallace WE

    更新日期:2001-09-15 00:00:00

  • Lactate dehydrogenase isoenzymes in hamster lung lavage fluid after lung injury.

    abstract::Lactate Dehydrogenase Isoenzymes in Hamster Lung Lavage Fluid after Lung Injury. Beck, B. D., Gerson, B., Feldman, H. A., and Brain, J. D. (1983). Toxicol. Appl. Pharmacol. 71, 59-71. Lactate dehydrogenase (LD) levels and isoenzyme patterns were determined in the cell-free supernatant fractions of lung lavage fluid fr...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Beck BD,Gerson B,Feldman HA,Brain JD

    更新日期:1983-10-01 00:00:00

  • Time-varying conjugation of 7,12-dimethylbenz[a]anthracene metabolites in rainbow trout (Oncorhynchus mykiss).

    abstract::Sexually immature rainbow trout were dosed via gavage with 7,12-[14C]dimethylbenz[a]anthracene (DMBA) in order to study hepatic metabolite formation over time and at single and multiple doses. beta-Glucuronidase and aryl sulfatase hydrolyses of bile extracts and subsequent high-pressure liquid chromatography analysis ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Schnitz AR,Squibb KS,O'Connor JM

    更新日期:1993-07-01 00:00:00

  • CNS biochemical and pharmacological effects of the isomers of hexachlorocyclohexane (lindane) in the mouse.

    abstract::gamma-Hexachlorocyclohexane (gamma-HCH), the active ingredient of the insecticide lindane, has been shown to be a seizure-inducing agent in mammals. gamma-HCH and two non-convulsant isomers of HCH (alpha and delta) were compared as to their CNS-related pharmacological and biochemical effects. gamma-HCH was a potent se...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Fishman BE,Gianutsos G

    更新日期:1988-03-30 00:00:00

  • Effects of vehicle on the uptake and elimination kinetics of capsaicinoids in human skin in vivo.

    abstract::While the physiologic and molecular effects of capsaicinoids have been extensively studied in various model systems by a variety of administration routes, little is known about the uptake and elimination kinetic profiles in human skin following topical exposure. The present study evaluated the uptake and elimination k...

    journal_title:Toxicology and applied pharmacology

    pub_type: 临床试验,杂志文章


    authors: Pershing LK,Reilly CA,Corlett JL,Crouch DJ

    更新日期:2004-10-01 00:00:00

  • 2,6-Dithiopurine, a nucleophilic scavenger, protects against mutagenesis in mouse skin treated in vivo with 2-(chloroethyl) ethyl sulfide, a mustard gas analog.

    abstract::Sulfur mustard [bis(2-chloroethyl)sulfide, SM] is a well-known DNA-damaging agent that has been used in chemical warfare since World War I, and is a weapon that could potentially be used in a terrorist attack on a civilian population. Dermal exposure to high concentrations of SM produces severe, long-lasting burns. To...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Boulware S,Fields T,McIvor E,Powell KL,Abel EL,Vasquez KM,MacLeod MC

    更新日期:2012-09-01 00:00:00

  • The fate of isoprene inhaled by rats: comparison to butadiene.

    abstract::Isoprene (2-methyl-1,3-butadiene), a volatile monomer occurring in the natural environment and used in the manufacture of elastomers, is a close chemical relative of the animal carcinogen 1,3-butadiene. To obtain toxicokinetic data for inhaled isoprene, male F344 rats were exposed in groups of 30 to 14C-labeled isopre...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Dahl AR,Birnbaum LS,Bond JA,Gervasi PG,Henderson RF

    更新日期:1987-06-30 00:00:00

  • Hemocompatibility and biocompatibility of antibacterial biomimetic hybrid films.

    abstract::In previous work, we developed novel antibacterial hybrid coatings based on dextran containing dispersed Ag NPs (~5 nm, DEX-Ag) aimed to offer dual protection against two of the most common complications associated with implant surgery, infections and rejection of the implant. However, their blood-material interaction...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Coll Ferrer MC,Eckmann UN,Composto RJ,Eckmann DM

    更新日期:2013-11-01 00:00:00

  • Application of hepatic cytochrome b5/P450 reductase null (HBRN) mice to study the role of cytochrome b5 in the cytochrome P450-mediated bioactivation of the anticancer drug ellipticine.

    abstract::The anticancer drug ellipticine exerts its genotoxic effects after metabolic activation by cytochrome P450 (CYP) enzymes. The present study has examined the role of cytochrome P450 oxidoreductase (POR) and cytochrome b5 (Cyb5), electron donors to P450 enzymes, in the CYP-mediated metabolism and disposition of elliptic...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Reed L,Indra R,Mrizova I,Moserova M,Schmeiser HH,Wolf CR,Henderson CJ,Stiborova M,Phillips DH,Arlt VM

    更新日期:2019-03-01 00:00:00

  • Generation of reactive dysmorphogenic intermediates by rat embryos in culture: effects of cytochrome P-450 inducers.

    abstract::We have investigated the capacity of cultured whole rat embryos to convert 2-acetylaminofluorene (AAF) to reactive metabolites capable of eliciting dysmorphogenic effects in the same embryos. Cultured embryos (Sprague-Dawley) were exposed to AAF for periods of 2 or 24 hr, after which metabolites were isolated from the...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Juchau MR,Bark DH,Shewey LM,Greenaway JC

    更新日期:1985-12-01 00:00:00

  • Moving into advanced nanomaterials. Toxicity of rutile TiO2 nanoparticles immobilized in nanokaolin nanocomposites on HepG2 cell line.

    abstract::Immobilization of nanoparticles on inorganic supports has been recently developed, resulting in the creation of nanocomposites. Concerning titanium dioxide nanoparticles (TiO2 NPs1), these have already been developed in conjugation with clays, but so far there are no available toxicological studies on these nanocompos...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Bessa MJ,Costa C,Reinosa J,Pereira C,Fraga S,Fernández J,Bañares MA,Teixeira JP

    更新日期:2017-02-01 00:00:00

  • Aliskiren toxicity in juvenile rats is determined by ontogenic regulation of intestinal P-glycoprotein expression.

    abstract::Juvenile rat toxicity studies with the direct renin inhibitor aliskiren were initiated to support treatment in the pediatric population. In Study 1, aliskiren was administered orally to juvenile rats at doses of 0, 30, 100 or 300 mg/kg/day with repeated dosing from postpartum day (PPD) 8 to PPD 35/36. In-life, clinica...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Hoffmann P,Beckman D,McLean LA,Yan JH

    更新日期:2014-02-15 00:00:00

  • A study on the biochemical and biological behavior of methylmercury.

    abstract::The biochemical and biological behavior of methylmercury (MeHg) was investigated by measurement of MeHg release rate from erythrocytes (RBC) of selected animal strains and species, by measurement of the intracellular distribution of MeHg in RBC, and by measurement of the binding affinity of hemoglobin (Hb) for MeHg. M...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Doi R,Tagawa M

    更新日期:1983-07-01 00:00:00

  • Sexually dimorphic gene regulation in brain as a target for endocrine disrupters: developmental exposure of rats to 4-methylbenzylidene camphor.

    abstract::The developing neuroendocrine brain represents a potential target for endocrine active chemicals. The UV filter 4-methylbenzylidene camphor (4-MBC) exhibits estrogenic activity, but also interferes with the thyroid axis. We investigated effects of pre- and postnatal exposure to 4-MBC in the same rat offspring at brain...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Maerkel K,Durrer S,Henseler M,Schlumpf M,Lichtensteiger W

    更新日期:2007-01-15 00:00:00

  • All-trans retinoic acid protects against arsenic-induced uterine toxicity in female Sprague-Dawley rats.

    abstract:BACKGROUND AND PURPOSE:Arsenic exposure frequently leads to reproductive failures by disrupting the rat uterine histology, hormonal integrity and estrogen signaling components of the rat uterus, possibly by generating reactive oxygen species. All-trans retinoic acid (ATRA) was assessed as a prospective therapeutic agen...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Chatterjee A,Chatterji U

    更新日期:2011-12-01 00:00:00

  • Protective effects of melittin on transforming growth factor-β1 injury to hepatocytes via anti-apoptotic mechanism.

    abstract::Melittin is a cationic, hemolytic peptide that is the main toxic component in the venom of the honey bee (Apis mellifera). Melittin has multiple effects, including anti-bacterial, anti-viral and anti-inflammatory, in various cell types. However, the anti-apoptotic mechanisms of melittin have not been fully elucidated ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Lee WR,Park JH,Kim KH,Park YY,Han SM,Park KK

    更新日期:2011-10-15 00:00:00

  • Minimal basal activity and lack of metal-induced activation of the metallothionein gene correlates with lobe-specific sensitivity to the carcinogenic effects of cadmium in the rat prostate.

    abstract::Metallothionein (MT), a high-affinity metal-binding protein, is known to detoxicate cadmium and may play an important role in cadmium carcinogenesis. In the rat, the ventral lobe of the prostate is sensitive to cadmium carcinogenesis, while the dorsolateral lobe is refractory. The possibility exists that the basis of ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Coogan TP,Shiraishi N,Waalkes MP

    更新日期:1995-05-01 00:00:00

  • Computer simulation of the lactational transfer of tetrachloroethylene in rats using a physiologically based model.

    abstract::A physiologically based pharmacokinetic (PBPK) model describing transfer of inhaled tetrachloroethylene (PCE) into breast milk with the consequent exposure of the nursing pups was developed and validated in lactating rats. The PBPK model was based on partition coefficients (PCs), which were determined by the equilibra...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Byczkowski JZ,Kinkead ER,Leahy HF,Randall GM,Fisher JW

    更新日期:1994-04-01 00:00:00

  • Gallium arsenide augments antigen processing by peritoneal macrophages for CD4+ helper T cell stimulation.

    abstract::Gallium arsenide (GaAs) suppresses numerous immunologic functions of leukocytes at distal locations from the exposure site. The effect of direct GaAs exposure on peritoneal cells was examined by i.p. administration of the chemical. No alteration in the frequency of various cell lineages, including macrophages, B cells...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Hartmann CB,McCoy KL

    更新日期:1996-12-01 00:00:00

  • Glutathione depletion by methyl chloride and association with lipid peroxidation in mice and rats.

    abstract::Inhalation of methyl chloride (CH3Cl) by male B6C3F1 mice resulted in a concentration-dependent depletion of glutathione (GSH) in liver, kidney, and brain. Exposure for 6 hr to 100 ppm CH3Cl decreased the concentration of GSH in mouse liver by 45%, while exposure to 2500 ppm for 6 hr lowered liver GSH to approximately...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Kornbrust DJ,Bus JS

    更新日期:1984-03-15 00:00:00