Abstract：
:Early hepatocyte death occurs in most liver injury cases and triggers liver inflammation, which in combination with other risk factors leads to the development of liver disease. However, the pathogenesis of early phase hepatocyte death remains poorly understood. Here, C57BL/6J mice were treated with the hepatotoxic drug flucloxacillin (FLUX) and the toll-like receptor 9 agonist CpG oligodeoxynucleotide (ODN) to reproduce the early phase of drug-induced hepatotoxicity and investigate its pathogenesis. C57BL/6J mice were treated with FLUX (100 mg/kg, gavage) alone or in combination with ODN (40 μg/mouse, intraperitoneally). Plasma alanine aminotransferase (ALT) level was measured as a marker of hepatotoxicity. FLUX or ODN alone was insufficient to induce ALT elevation, whereas combination treatment with FLUX and ODN increased ALT levels 24 h after FLUX treatment and upregulated Fas ligand in natural killer T (NKT) cells and Fas in hepatocytes. FLUX induced mitochondrial permeability transition (MPT), and pretreatment with ODN sensitized mitochondria to FLUX-induced MPT. The increase in ALT levels induced by ODN and FLUX co-treatment was suppressed in Fas ligand (gld/gld)-deficient mice and in mice deficient in a component of MPT pore opening (cyclophilin D-knockout mice). These results suggested that ODN activated the Fas/Fas ligand-mediated pathway in NKT cells and hepatocytes, which may predispose to FLUX-induced mitochondrial dysfunction and lead to early phase hepatocyte apoptosis. Taken together, these findings elucidate a potentially novel mechanism underlying drug-induced early phase hepatocyte death related to the Fas/Fas ligand death receptor pathway and mitochondrial dysfunction.
journal_name
Arch Toxicoljournal_title
Archives of toxicologyauthors
Song B,Aoki S,Liu C,Ito Kdoi
10.1007/s00204-019-02454-1subject
Has Abstractpub_date
2019-06-01 00:00:00pages
1573-1584issue
6eissn
0340-5761issn
1432-0738pii
10.1007/s00204-019-02454-1journal_volume
93pub_type
杂志文章abstract：:Reduced gluconeogenesis due to decreased activity of key gluconeogenic enzymes in liver, together with feed refusal, has been suggested to play an important role in 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced lethality in rats. This study was carried out to further analyse the toxicological significance of red...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040050626
更新日期：1999-08-01 00:00:00
abstract：:Environmental tobacco smoke (ETS) is associated with high morbidity and mortality, mainly in children. However, few studies focus on the brain development effects of ETS exposure. Myelination mainly occurs in the early years of life in humans and the first three postnatal weeks in rodents and is sensitive to xenobioti...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-014-1343-2
更新日期：2015-11-01 00:00:00
abstract：:In the isolated liver transient perfusion without calcium results in cholestasis which was characterized by an increased efflux rate across the sinusoidal membrane and inhibition of the concentrative transport of bromosulfophthalein to the canalicular side of the cell. Cholestasis could not be reversed within the usua...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00303180
更新日期：1980-03-01 00:00:00
abstract：:The effects of equimolar doses of the triphenylethylene antiestrogens tamoxifen and toremifene on female Sprague-Dawley rat liver were studied in a 52-week toxicity study which included a 13-week recovery period. Liver tumors were found in four out of five rats at the highest dose level of tamoxifen (45 mg/kg per day)...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF02072035
更新日期：1993-01-01 00:00:00
abstract：:Female C57/BL/6 x DBA/2 hybrid mice were exposed to two concentrations (270 and 135 ppm) of tetrachloroethylene (PER) in inhalation chambers for 6 h/day, 5 days per week, up to 11.5 weeks (270 ppm) and 7.5 weeks (135 ppm), respectively, followed by a 3-week exposure-free period. In the peripheral blood a reduction of ...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF01974021
更新日期：1992-01-01 00:00:00
abstract：:Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions. Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage. Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-012-0916-1
更新日期：2013-02-01 00:00:00
abstract：:The present experiments were performed to test the possibility of interrupting the enterohepatic circulation of arsenic (As). Therefore the efficacy of adsorbents to bind As and/or As-DMPS adducts in vitro and their effect on the excretion of As into the feces and urine in vivo were investigated after injection of As2...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040050237
更新日期：1995-01-01 00:00:00
abstract：:The effect of pretreatment with cadmium (Cd) complexes on the distribution and accumulation of Cd in the liver and kidneys was examined for the Cd complexes that are reabsorbed site-selectively at the renal proximal tubules of rats. Cd was administered simultaneously with excess cysteine or as metallothionein (MT) and...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00297117
更新日期：1986-04-01 00:00:00
abstract：:Etoposide (ETP) and anthracyclines are applied for wide anti-cancer treatments. However, the ETP-induced cardiotoxicity remains to be a major safety issue and the underlying cardiotoxic mechanisms are not well understood. This study is aiming to unravel the cardiotoxicity profile of ETP in comparison to anthracyclines...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-018-2170-7
更新日期：2018-04-01 00:00:00
abstract：:This study aimed to investigate the effect of single and repeated administration of fenarimol on murine liver, kidney and lung microsomal CYP-catalyzed drug metabolism. The modulation of the regio- and stereo-selective hydroxylation of testosterone by fenarimol was considered in evaluating cocarcinogenic properties. I...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040050298
更新日期：1996-01-01 00:00:00
abstract：:A series of experiments was set up to elucidate the effects of pollution on marine and estuarine fish health, since the European flounder (Platichthys flesus) has shown a relatively high prevalence of (pre)neoplastic liver lesions and lymphocystis virus disease in Dutch coastal and estuarine waters. The hypothesis of ...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040100213
更新日期：2001-04-01 00:00:00
abstract：:UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isofo...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-020-02765-8
更新日期：2020-08-01 00:00:00
abstract：:Second order rate constants for the initial reaction of 12 mammalian oxyhemoglobins (Hb) with equimolar phenylhydrazine (PHZ), a compound inducing Heinz body hemolytic anemia, were determined by recording continuous changes in absorbance with time at 577 nm. The rate constants were varied in a range from 43 m-1.s-1 wi...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040050161
更新日期：1995-01-01 00:00:00
abstract：:The ethylene oxide adduct formed on the N-terminal valine in haemoglobin was investigated as a biological monitor of tobacco smoke intake. The modified method developed for the determination of the hydroxyethylvaline adduct (HOEtVal) involved reaction of globin with pentafluorophenyl isothiocyanate, extraction of the ...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00332482
更新日期：1988-01-01 00:00:00
abstract：:The effects of diabetes on cytochrome P450 (CYP)-dependent drug metabolizing enzymes are yet to be clarified. The most widely used animals in these studies have been rats, and information on the effects of diabetes on rabbit liver drug metabolizing enzymes have been unavailable until now. In this study, for the first ...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-005-0654-8
更新日期：2005-08-01 00:00:00
abstract：:Female wistar rats, conventional albino mice, and Chinese hamsters were given a single dose of acrylonitrile, 0.5 or 0.75 mM/kg body weight. The elimination in the urine of thiocyanate, which is the main metabolite of acrylonitrile, indicated a decreasing proportion of biotransformation after oral (over 20%), intraper...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00353240
更新日期：1975-02-14 00:00:00
abstract：:Previously we reported that exposure of mouse and human mast cells to aryl hydrocarbon receptor (AhR) ligands resulted in reactive oxygen species (ROS)- and calcium (Ca2+)-dependent activation of mast cells in vitro and in vivo. However, the mechanisms through which the AhR-ligand axis mediates stress response, Ca2+ s...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-016-1861-1
更新日期：2017-04-01 00:00:00
abstract：:Amanita phalloides is responsible for more than 90 % of mushroom-related fatalities, and no effective antidote is available. α-Amanitin, the main toxin of A. phalloides, inhibits RNA polymerase II (RNAP II), causing hepatic and kidney failure. In silico studies included docking and molecular dynamics simulation couple...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-015-1582-x
更新日期：2015-12-01 00:00:00
abstract：:Previous studies in our laboratory identified retinoid-induced defects that are mediated by RAR-RXR heterodimerization using interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in mice (Elmazar et al. 1997, Toxicol Appl Pharmacol 146:21-28; Elmazar et al. 2001, Toxicol Appl Pharmacol 170:...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-004-0586-8
更新日期：2004-11-01 00:00:00
abstract：:The high acute toxicity of acrylonitrile may be a result of its intrinsic biological reactivity or of its metabolite cyanide. Intravenous N-acetylcysteine has been recommended for treatment of accidental intoxications in acrylonitrile workers, but such recommendations vary internationally. Acrylonitrile is metabolized...
journal_title：Archives of toxicology
pub_type： 杂志文章,评审
doi：10.1007/s002040000109
更新日期：2000-07-01 00:00:00
abstract：:Knowledge about established breast carcinogens can support improved and modernized toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages, and evidence overall supports a linear dose-respons...
journal_title：Archives of toxicology
pub_type： 杂志文章,评审
doi：10.1007/s00204-020-02752-z
更新日期：2020-05-01 00:00:00
abstract：:The toxicokinetics of the four stereoisomers of the nerve agent C(+/-)P(+/-)-soman was analysed in cerebrospinal fluid (CSF) and blood in anaesthetized, spontaneously breathing pigs during a 90-min period after injection of soman. The pigs were challenged with different intravenous (i.v.) doses of C(+/-)P(+/-)-soman c...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040050529
更新日期：1998-07-01 00:00:00
abstract：:Our previous study suggested the possibilities that dicyclanil (DC), a nongenotoxic carcinogen, produces oxidative stress in the liver of the two-stage hepatocarcinogenesis model of mice and the stress induced probably causes secondary oxidative DNA damage. However, clear evidences demonstrating the relationship betwe...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-006-0086-0
更新日期：2006-10-01 00:00:00
abstract：:Neuropathy Target Esterase (NTE) was initially identified as the primary target esterase of some organophosphorus compounds that cause delayed neuropathy. Some studies in vivo suggest that this protein may also perform a function in embryonic development and therefore also in cell differentiation. The aim of this work...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-010-0518-8
更新日期：2010-06-01 00:00:00
abstract：:Cadmium-induced metallothionein (MT) synthesis was investigated in male rats of three ages, 3, 12 and 24 months. Physiological levels of MT in kidney, liver and lung measured simultaneously in untreated animals were found to be within the same range in all three age groups. Following 3-day treatment with CdCl2 equival...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00293629
更新日期：1988-01-01 00:00:00
abstract：:Previous rat toxicity studies of alpha-glycosyl isoquercitrin (AGIQ), a water-soluble flavonol glycoside derived from rutin, revealed systemic yellow bone discoloration. This investigative study was conducted to determine the AGIQ metabolite(s) responsible for the discoloration. Female Sprague-Dawley rats were adminis...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-020-02760-z
更新日期：2020-07-01 00:00:00
abstract：:The investigation was aimed at providing insight into the side chain metabolism of furazolidone in mice. The agents used in the experiments were furazolidone, 3-amino-2-oxazolidinone, oxazolidinone, nitrofurantoin, 3-aminohydantoin and hydantoin, administered intraperitoneally at five equimolar doses ranging from 0.17...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00661377
更新日期：1987-12-01 00:00:00
abstract：:The highly directional maternal-to-fetal transfer of essential fatty acids (EFAs) across the placenta plays a critical role in guiding proper fetal development. Exposure to xenobiotics that may alter the fetal supply of EFAs/lipids could lead to fetal toxicity. Since the placenta is the first fetal arising organ that ...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-005-0047-z
更新日期：2006-05-01 00:00:00
abstract：:Fulminant hepatitis is a serious inflammatory condition of the liver characterized by massive necrosis of liver parenchyma following excessive immune cell infiltration into the liver, and possibly causing sudden hepatic failure and medical emergency. However, the underlying mechanisms are not fully understood. Here, w...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-019-02633-0
更新日期：2020-02-01 00:00:00
abstract：:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent tumor promoter ever tested in rodents. Although it is known that most of the effects of TCDD are mediated by binding to the aryl hydrocarbon receptor (AhR), the mechanisms leading to tumor promotion still remain to be elucidated. Loss of contact inhibition ...
journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-004-0601-0
更新日期：2005-01-01 00:00:00
