Abstract：
:Troglitazone (Tro) is a thiazolidinedione antidiabetic drug that was withdrawn from the market due to its association with idiosyncratic severe liver injury. Tro has never induced liver injury in experimental animals in vivo. It was assumed that the species differences between human and experimental animals in the pharmaco- or toxicokinetics of Tro might be associated with these observations. In this study, we investigated whether a chimeric mouse with a humanized liver that we previously established, whose replacement index with human hepatocytes is up to 92% can reproduce Tro-induced liver injury. When the chimeric mice were orally administered Tro for 14 or 23 days (1000mg/kg/day), serum alanine aminotransferase (ALT) was significantly increased by 2.1- and 3.6-fold, respectively. Co-administration of l-buthionine sulfoximine (10mM in drinking water), an inhibitor of glutathione (GSH) synthesis, unexpectedly prevented the Tro-dependent increase of ALT, which suggests that the GSH scavenging pathway will not be involved in Tro-induced liver injury. To elucidate the mechanism of the onset of liver injury, hepatic GSH content, the level of oxidative stress markers and phase I and phase II drug metabolizing enzymes were determined. However, these factors were not associated with Tro-induced liver injury. An immune-mediated reaction may be associated with Tro-induced liver toxicity in vivo, because the chimeric mouse is derived from an immunodeficient SCID mouse. In conclusion, we successfully reproduced Tro-induced liver injury using chimeric mice with a humanized liver, which provides a new animal model for studying idiosyncratic drug-induced liver injury.
journal_name
Toxicol Lettjournal_title
Toxicology lettersauthors
Kakuni M,Morita M,Matsuo K,Katoh Y,Nakajima M,Tateno C,Yokoi Tdoi
10.1016/j.toxlet.2012.08.001subject
Has Abstractpub_date
2012-10-02 00:00:00pages
9-18issue
1eissn
0378-4274issn
1879-3169pii
S0378-4274(12)01237-4journal_volume
214pub_type
杂志文章abstract：:The aim of this study was to establish an air-liquid interface (ALI) culture of precision-cut lung slices (PCLS) for direct exposure of lung cells to gaseous contaminants. Nitrogen dioxide (NO(2)) and ozone (O(3)) were selected as model gas compounds. Acute pro-inflammatory and toxic effects of NO(2) and O(3) on live ...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2010.04.004
更新日期：2010-07-01 00:00:00
abstract：:The skin absorption of aniline, aniline with 3% water content, and 1 and 2% aqueous aniline solutions was investigated in man. The time of exposure was 30 or 60 min. The absorbed amount of aniline was calculated on the basis of rho-aminophenol excretion in 24-h urine. The rate of aniline absorption from aqueous soluti...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(82)90231-4
更新日期：1982-03-01 00:00:00
abstract：:We investigated the effect of copper on cadmium-induced cytotoxicity on vascular endothelial cells from bovine aorta in a culture system. Cytotoxicity was evaluated by the [3H]adenine release assay and the histological observation. After a 24-h incubation, cadmium exhibited a significant cytotoxicity on confluent cult...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(92)90103-q
更新日期：1992-10-01 00:00:00
abstract：:The effect of carbon monoxide (CO) on pulmonary glutathione-S-transferase (GST) activity was investigated using the isolated perfused rabbit lung (IPRL) preparation. CO at a concentration of 7.5% did not alter the conjugation of glutathione (GSH) with 1,2-epoxy-(p-nitrophenoxy)propane (ENP) in the IPRL. The rate of GS...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(90)90164-h
更新日期：1990-06-01 00:00:00
abstract：:L-Carnitine is a critical metabolite indispensable for the metabolism of lipids as it facilitates fatty acid transport into the mitochondrion where β-oxidation occurs. Human astrocytes (CCF-STTG1 cells) and hepatocytes (HepG2 cells) exposed to aluminum (Al) and hydrogen peroxide (H₂O₂), were characterized with lower l...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2011.03.019
更新日期：2011-06-24 00:00:00
abstract：:Exposure to cyanide from gari, a popular cassava food in West Africa, is implicated in the causation of ataxic polyneuropathy and amblyopia, but this has been questioned because cyanide was not detected in gari in a study. This study was carried out to determine if gari is a source of exposure to cyanide. Gari (150 g)...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/s0378-4274(02)00232-1
更新日期：2002-09-05 00:00:00
abstract：:Environmental exposure to the highly persistent chlorinated pesticides including dieldrin and lindane is postulated to be a risk factor to the development of Parkinson's disease, a devastating movement disorder. We have previously reported that the combined treatment with dieldrin and lindane induces a cooperative tox...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2018.09.006
更新日期：2018-12-15 00:00:00
abstract：:Dioxins are metabolized by cytochrome P450, family 1 (CYP1) via the aromatic hydrocarbon receptor (AHR). We determined whether different blood dioxin concentrations are associated with polymorphisms in AHR (dbSNP ID: rs2066853), AHR repressor (AHRR; rs2292596), CYP1 subfamily A polypeptide 1 (CYP1A1; rs4646903 and rs1...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2013.03.013
更新日期：2013-06-07 00:00:00
abstract：:The early histologic lesions and sequential changes in the development of mirex-induced cataracts were studied in the offspring of lactating female Sherman rats given oral doses of mirex for 5 consecutive days post partum. The earliest histologic change, seen at neonatal day 7, was slight swelling of the individual co...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(81)90163-6
更新日期：1981-11-01 00:00:00
abstract：:Uncertainty in risk assessment can be reduced by increasing the use of relevant data specific to the particular xenobiotic and exposed organism. We describe the development of a preliminary, mechanism-based exposure response model for chloroform hepatotoxicity consistig of toxicokinetic (TK) and toxicodynamic (TD) sub...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(95)03528-1
更新日期：1995-12-01 00:00:00
abstract：:Cellular senescence is characterized by irreversible cell arrest and is associated with the development of chronic diseases, including cancer. Here, we investigated the induction of cellular senescence during liver carcinogenesis. Liver cancer was induced in Fischer 344 rats with a weekly intraperitoneal injection of ...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2015.11.011
更新日期：2016-01-22 00:00:00
abstract：:Benzene is a human leukemogen, and a bone marrow toxin and carcinogen in experimental animals. The reactive intermediates involved in benzene toxicity and their mechanism(s) of action have not been clearly delineated. We have investigated the clastogenic and cytotoxic effects of trans,trans-muconaldehyde (MUC), a reac...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/s0378-4274(01)00340-x
更新日期：2001-05-19 00:00:00
abstract：:The dose-response curve obtained in toxicity testing is a mirror image of the susceptibility distribution in the treated population, i.e. it follows increasing tolerance of the individuals to the adverse effects of the chemical under investigation. Defining a dose as a maximum tolerated exposure level, therefore, spli...
journal_title：Toxicology letters
pub_type： 杂志文章,评审
doi：10.1016/s0378-4274(01)00458-1
更新日期：2002-02-07 00:00:00
abstract：:Human fetuses and neonates are particularly vulnerable to methylmercury (MeHg)-induced brain damage and are sensitive even to low exposure levels. Previous work of our group evidence that prenatal exposure to MeHg causes cognitive and behavioral alterations and disrupt hippocampus signaling. The current study aimed to...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2017.12.006
更新日期：2018-03-01 00:00:00
abstract：:Xenobiotic exposure is a risk factor in the etiology of neurodegenerative disease. It was recently hypothesized that restricted exposure during brain development could predispose for a neurodegenerative disease later in life. As neuroinflammation contributes to progressive neurodegeneration, it is suspected that neuro...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2014.02.001
更新日期：2014-10-15 00:00:00
abstract：:In order to gain basic understanding in the ecotoxicity of endocrine disrupting chemicals or EDCs (including natural chemicals and some pharmaceuticals), many international research groups are currently testing these chemicals using aquatic invertebrates. This paper discusses relevant examples to address key questions...
journal_title：Toxicology letters
pub_type： 杂志文章,评审
doi：10.1016/s0378-4274(02)00046-2
更新日期：2002-05-10 00:00:00
abstract：:When pregnant mice were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the average time to eye opening in the offspring was shortened by about a day. How acceleration of eye opening by TCDD occurs remains unknown. To reveal the underlying mechanisms of the accelerated eye opening, pregnant mice were intraperit...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2010.04.001
更新日期：2010-07-01 00:00:00
abstract：:In vitro effects of mercury-selenium compounds, as compared with mercurials, against glucose-6-phosphate dehydrogenase (G6PD), catalase and trypsin were studied. Inhibitory potencies of two mercury-selenium (Hg-Se) compounds, bis(methylmercuric) selenide (BMS), and a reaction product of HgCl2, Na2SeO3 and glutathione ...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(82)90052-2
更新日期：1982-12-01 00:00:00
abstract：:The clinical use of gentamicin (G) is limited because of its nephrotoxic potential. The administration of G (50 mg/kg) to rats in a 10-day daily treatment gave a biphasic pattern of lactate dehydrogenase (LDH) and N-acetyl-beta-D-glucosaminidase (NAG) excretion. Alkaline phosphatase (ALP) was highly elevated during th...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(94)03163-2
更新日期：1995-01-01 00:00:00
abstract：:Toluene diisocyanate (TDI), a highly reactive industrial chemical is a leading cause of occupational asthma in westernized countries. It has also been reported to be a skin sensitizer in mice and guinea pigs although instances of skin sensitivity in humans are rare. It is uncertain if skin-contact is necessary to init...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/s0378-4274(01)00325-3
更新日期：2001-04-08 00:00:00
abstract：:Elevated urinary trehalase activity was observed in the inhabitants of the Jinzu River basin. Urinary trehalase activity was correlated with other urinalysis components, such as beta 2-microglobulin, glucose, amino nitrogen, and cadmium, of which a high level was observed in cadmium-polluted areas as compared with the...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(86)90206-7
更新日期：1986-12-01 00:00:00
abstract：:Pregnant mice of C57BL/6 and DBA/2 inbred strains were exposed to cigarette smoke during days 1-18 of pregnancy. Both mothers and offspring were killed at the age of 21-22 weeks, and ovaries were studied with respect to the number of primordial follicles and small primary follicles. In additional studies, 7,12-dimethy...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(85)90103-1
更新日期：1985-04-01 00:00:00
abstract：:Exposure to airborne particulate matter (PM) is a major risk factor for allergic airway inflammation such as asthma. Many of the PM components (i.e., polycyclic aromatic hydrocarbons and metals) are redox-active and capable of inducing cellular oxidative stress and injuries including inflammation and cell death. Airwa...
journal_title：Toxicology letters
pub_type： 杂志文章,评审
doi：10.1016/j.toxlet.2015.05.017
更新日期：2015-08-19 00:00:00
abstract：:Citrinin (CIT), a fungal metabolite causing nephrotoxicity, has a tolerable daily intake (TDI) value of 0.2μg/kg bw. Contamination of food with CIT is not sufficiently known to allow dietary exposure assessment. Urinary biomonitoring data are available from cohorts of several countries. However, kinetic information is...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2017.10.006
更新日期：2018-01-05 00:00:00
abstract：:Small molecular weight chemicals may irritate tissues via the induction of the production of various proinflammatory and chemotactic molecules. The structure of these irritants is heterogenous, as is the pattern of their effects. Chemicals are potentially allergenic (i.e. haptens) when they are able to bind proteins s...
journal_title：Toxicology letters
pub_type： 杂志文章,评审
doi：10.1016/0378-4274(96)03676-4
更新日期：1996-08-01 00:00:00
abstract：:Lead (Pb) exposure during development impairs a variety of cognitive, behavioral and neurochemical processes resulting in deficits in learning, memory, attention, impulsivity and executive function. Numerous studies have attempted to model this effect of Pb in rodents, with the majority of studies focusing on hippocam...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2016.01.011
更新日期：2016-03-30 00:00:00
abstract：:Reactivity of phenoxyl radicals towards biomolecules (proteins, nucleic acids and lipids) is essential for antioxidant (protective) versus prooxidant (cytotoxic) effects of phenolic compounds (antioxidants, phytochemicals, environmental pollutants and toxic chemicals). The present study demonstrates for the first time...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(96)03767-8
更新日期：1996-10-01 00:00:00
abstract：:The objective of this research was to develop a mathematical description of uptake of aromatic and aliphatic hydrocarbons into the stratum corneum of human skin in vivo. A simple description based on Fick's laws of diffusion was used to predict the spatiotemporal variation of naphthalene, 1- and 2-methylnaphthalene, u...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2008.03.005
更新日期：2008-05-30 00:00:00
abstract：:Indomethacin (IND) suppresses the T-dependent antibody response (TDAR) in juvenile males when it is administered to pregnant rats during late gestation. In this study, the effect of IND on cytokine production in juvenile rats was examined to investigate the mechanism behind the suppression of antibody production. IND ...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2008.11.013
更新日期：2009-02-25 00:00:00
abstract：:Recently, we reported that silver nanoparticles (AgNPs) induced reactive oxygen species (ROS) generation and the resultant oxidative stress contributes to the cell damage associated with AgNPs. 8-Oxoguanine (8-oxoG) is sensitive marker of ROS-induced DNA damage. 8-Oxoguanine DNA glycosylase 1 (OGG1) is an important DN...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2011.09.002
更新日期：2011-11-30 00:00:00
