Abstract:
:Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and hypotheses on potential mechanisms of action for this class of chemicals. Adult male CD-1 mice were exposed daily for 14 days to fluconazole, myclobutanil, propiconazole, or triadimefon at three dose levels by oral gavage. Doses were based on previous studies that resulted in liver hypertrophy or hepatotoxicity. All four triazoles caused hepatocyte hypertrophy, and all except triadimefon increased relative liver/body weight ratios at the middle and high dose levels. CYP enzyme activities were also induced by all four triazoles at the middle and high doses as measured by the dealkylations of four alkoxyresorufins, although some differences in substrate specificity were observed. Consistent with this common histopathology and biochemistry, several CYP and xenobiotic metabolizing enzyme (XME) genes were differentially expressed in response to all four (Cyp2d26 and Cyp3a11), or three of the four (Cyp2c40, Cyp2c55, Ces2, Slco1a4) triazoles. Differential expression of numerous other CYP and XME genes discriminated between the various triazoles, consistent with differences in CYP enzyme activities, and indicative of possible differences in mechanisms of hepatotoxicity or dose response. Multiple isoforms of Cyp1a, 2b, 2c, 3a, and other CYP and XME genes regulated by the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were differentially expressed following triazole exposure. Based on these results, we expanded on our original hypothesis that triazole hepatotoxicity was mediated by CYP induction, to include additional XME genes, many of which are modulated by CAR and PXR.
journal_name
Toxicol Appl Pharmacoljournal_title
Toxicology and applied pharmacologyauthors
Goetz AK,Bao W,Ren H,Schmid JE,Tully DB,Wood C,Rockett JC,Narotsky MG,Sun G,Lambert GR,Thai SF,Wolf DC,Nesnow S,Dix DJdoi
10.1016/j.taap.2006.02.016subject
Has Abstractpub_date
2006-09-15 00:00:00pages
274-84issue
3eissn
0041-008Xissn
1096-0333pii
S0041-008X(06)00088-3journal_volume
215pub_type
杂志文章abstract::Ethylnitrosourea (ENU) is a proven animal teratogen, although the mechanism of its developmental toxicity is unknown. The micromass rat embryo midbrain (CNS) and limb bud (LB) cultures were used in an effort to determine potential mechanisms by which ENU may exert its teratogenic effect. When cultured at high cell den...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(90)90295-6
更新日期:1990-06-15 00:00:00
abstract::Follicle growth culminates in ovulation, which allows for the expulsion of fertilizable oocytes and the formation of corpora lutea. Bisphenol A (BPA) is present in many consumer products, and it has been suggested that BPA impairs ovulation; however, the underlying mechanisms are unknown. Therefore, this study first e...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2015.10.010
更新日期:2015-12-15 00:00:00
abstract::Para-quinones such as 1,4-Benzoquinone (BQ) and menadione (MD) and ortho-quinones including the oxidation products of catecholamines, are derived from xenobiotics as well as endogenous molecules. The effects of quinones on major protein handling systems in cells; the 20/26S proteasome, the ER stress response, autophag...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2014.08.014
更新日期:2014-10-15 00:00:00
abstract::Air pollution particles (PM) are known to elicit an acute inflammatory response in vivo that is mediated in part through PM-induced activation of the NF-kappaB signaling pathway. Many of the details of this process and particularly where in the cell it occurs are unclear. To determine whether contact of PM particles w...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2005.01.013
更新日期:2005-10-01 00:00:00
abstract::The physiologically based dosimetry description for acrylonitrile (ACN) and its mutagenic epoxide metabolite 2-cyanoethylene oxide (CEO) in F-344 rats (M. L. Gargas, M. E. Anderson, S.K.O. Teo, R. Batra, T. R. Fennell, and G. L. Kedderis, 1995, Toxicol. Appl. Pharmacol. 134, 185-194) has been refined to include a phys...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1996.0239
更新日期:1996-10-01 00:00:00
abstract::To assess aluminum toxicity to the A1-exposed lactating organism and her suckling offspring, lactating rabbits received 20, sc, A1 lactate injections (0, 25, 100, 400, or 800 mumol A1/kg/inj) between Days 4 and 29 postpartum. Offspring were weaned Day 30 postpartum. Weight gain in the first 12 postnatal weeks was slig...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(84)90073-5
更新日期:1984-08-01 00:00:00
abstract::Metallothioneins (MTs) are ubiquitous low-molecular-weight proteins that are induced by a variety of inducers, including metals, lipopolysaccharides (LPS), cytokines, oxidative stress, etc., and are thought to play a protective role against various toxic insults. The constitutive level of metallothionein is an importa...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1995.1056
更新日期:1995-03-01 00:00:00
abstract::To clarify the immunotoxicity of benzene, the effects of benzene inhalation on T and B lymphocytes and immune responses in mice were examined. BALB/c male mice were exposed to 50 or 200 ppm benzene vapor, 6 hr/day for 7 or 14 consecutive days. T and B lymphocytes, in blood and spleen, were detected by the cytotoxicity...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(86)90390-x
更新日期:1986-08-01 00:00:00
abstract::The ASCT2 transport system catalyses a sodium-dependent antiport of glutamine and other neutral amino acids which is involved in amino acid metabolism. A library of 1,2,3-dithiazoles was designed, synthesized and evaluated as inhibitors of the glutamine/amino acid ASCT2 transporter in the model system of proteoliposom...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2012.09.011
更新日期:2012-11-15 00:00:00
abstract::Electrophiles, ubiquitously found in the environment, modify thiol groups of sensor proteins, leading to activation of redox signaling pathways such as the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2 related factor 2 (Nrf2) pathway. Nrf2 activation by exposure to single electrophiles has been establi...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2020.115392
更新日期:2021-01-09 00:00:00
abstract::Chronic inhalation of high concentrations of respirable quartz particles has been implicated in various lung diseases including lung fibrosis and cancer. Generation of reactive oxygen species (ROS) and oxidative stress is considered a major mechanism of quartz toxicity. Curcumin, a yellow pigment from Curcuma longa, h...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2007.10.002
更新日期:2008-02-15 00:00:00
abstract::Epidemiological studies indicate that low levels of polychlorinated biphenyl (PCB) exposure can adversely affect neurocognitive development. In animal models, perturbations in calcium signaling, neurotransmitters, and thyroid hormones have been postulated as potential mechanisms for PCB-induced developmental neurotoxi...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2008.04.023
更新日期:2008-09-01 00:00:00
abstract::The effect of T2-toxin on DNA and protein synthesis was investigated, both in vivo and in vitro. For mice which had been submitted to different treatment schedules (single dose, 3-, or 7-day treatment), the rate of DNA and protein biosynthesis was measured in thymus, bone marrow, liver, and spleen cells. T2-toxin inhi...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(83)90104-7
更新日期:1983-09-15 00:00:00
abstract::The effect of maternal selenium deficiency on methyl mercury fetotoxicity was examined in the ICR strain of mice. Pregnant mice were fed either selenium-deficient diets based on torula yeast or selenium-supplemented diets which were identical to the former except that 0.1, 0.2, or 0.4 mg of selenium per kilogram of di...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(87)90207-9
更新日期:1987-05-01 00:00:00
abstract::Interleukin-6 (IL-6) is a central mediator of immunotoxicity that is associated with exposure to the trichothecene vomitoxin (VT). The purpose of this investigation was to test the hypothesis that the inducible cyclooxygenase-2 (COX-2) and its metabolites contribute to VT-induced IL-6 upregulation. VT at 100 to 250 ng...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/s0041-008x(02)00033-9
更新日期:2003-03-01 00:00:00
abstract::Montelukast (MK),a cysteinyl leukotriene (CysLT1) receptor antagonist, latterly exhibited a remarkable neuroprotective activity in various neurodegenerative disorders. This study aims to elucidate the neuroprotective effect of MK in rotenone-induced Parkinson's disease(PD) model in rats. Ninety six male rats were spli...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2018.09.012
更新日期:2018-11-01 00:00:00
abstract::The length distributions of single fibrils of Coalinga, UICC-B and wet dispersed chrysotile were measured by transmission electron microscopy (TEM). It was found that the distributions significantly diverged above approximately 10 μm (μm) in length, corresponding to differences in published results of animal experimen...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2018.08.010
更新日期:2018-12-15 00:00:00
abstract::Intravenous administration of drug-loaded polyalkylcyanoacrylate (PACA) nanoparticles is followed by a rapid uptake by the tissues of the reticuloendothelial system, mainly the liver. Nevertheless, it is so far unknown whether chronic administration of nanoparticles can lead to damage to the liver cells. We have studi...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1995.1032
更新日期:1995-02-01 00:00:00
abstract::The cDNA sequences for two dioxin-inducible cytochrome P450s in chicken, CYP1A4 and CYP1A5, have recently been reported which correspond to two dioxin-inducible forms of P450 previously designated as TCDDAHH and TCDDAA, respectively. The developmental expression of CYP1A4-associated aryl hydrocarbon (benzo[a]pyrene) h...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1998.8439
更新日期:1998-07-01 00:00:00
abstract::Acetaminophen (APAP) administration (600 mg/kg, ip) to 18-hr fasted, 3-month-old male CD-1 mice results in necrosis of the convoluted renal proximal tubules with a corresponding elevation of plasma urea nitrogen (BUN). Administration of the gamma-glutamyl transpeptidase inhibitor, L-(alpha S,5S)-alpha-amino-3-chloro-4...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1996.0020
更新日期:1996-01-01 00:00:00
abstract::Exposure of mice to cationic rhodamines, Rh 123 and Rh 6G, has been found to be associated with developmental toxicity, while neutral rhodamines (e.g., Rh B) had no such effect. When mouse embryos from dams given ip injections of Rh 123, Rh 6G (15 mg/kg), or Rh B (30 mg/kg) on gestation Day (GD) 10 were examined, Rh 1...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(89)90113-0
更新日期:1989-06-01 00:00:00
abstract::The high affinity metal-binding protein metallothionein (MT) is thought to detoxify cadmium (Cd) but appears to be deficient in several known targets of Cd carcinogenesis. The rat ventral prostate (VP) was recently identified as one of these target tissues. The nature of the Cd-binding proteins in the prostate has not...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(89)90214-7
更新日期:1989-10-01 00:00:00
abstract::The effect of butylated hydroxytoluene (BHT), which is used widely as an antioxidant, on IgE-dependent allergic responses in vivo and in vitro was investigated. For in vivo study, passive cutaneous anaphylaxis (PCA) was elicited in rats by i.d. injection of anti-DNP IgE and 48 h later by i.v. injection of DNP-HSA. BHT...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2007.05.007
更新日期:2007-09-01 00:00:00
abstract::The use of isocyanates in industry has been increasing and, therefore, the potential for human exposure has also increased. Two such isocyanates are diphenylmethane-4,4'-diisocyanate (MDI) and dicyclohexylmethane-4,4'-diisocyanate (SMDI). Furthermore, there are only a few reports describing the toxicity of these diiso...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(85)90182-6
更新日期:1985-03-15 00:00:00
abstract::Reviewing available data shows that most of antipsychotic drugs are associated with arrhythmia and sudden death. Experimental studies have shown a HERG channel blockade, a dose-dependent increase in duration of action potential or of QT interval, with various degrees of indicators of serious arrhythmogenicity. However...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2004.03.016
更新日期:2004-08-15 00:00:00
abstract::The Adverse Outcome Pathway (AOP) framework describes the progression of a toxicity pathway from molecular perturbation to population-level outcome in a series of measurable, mechanistic responses. The controlled, computer-readable vocabulary that defines an AOP has the ability to, automatically and on a large scale, ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2018.02.006
更新日期:2018-03-15 00:00:00
abstract::Nutrient availability is one of the major non-genetic factors determining embryonic growth and larval or fetal size. Due to the high human consumption of blood lipid regulators, fibrates have recently been reported as pollutants in rivers. Our study investigated the developmental toxicity of fibrates in zebrafish. Tre...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2007.11.016
更新日期:2008-05-01 00:00:00
abstract::Female Golden Syrian hamsters, F-344 rats, Swiss CD-1 mice, and B6C3F1 hybrid mice were exposed 6 hr/day, 5 days/week to carcinogenic levels of vinyl chloride (VC) for 6, 12, 18, or 24 months (rats and hamsters only). Other groups of rodents were held for 6 or 12 months and then exposed for 6 or 12 months. At the end ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(83)90361-7
更新日期:1983-03-30 00:00:00
abstract:BACKGROUND:Bleeding episodes commonly occur in patients on warfarin treatment even in those within therapeutic range of international normalized ratio (INR). The objective of this study was to investigate the effects of the 8 examined polymorphisms on the risk of bleeding complications in a sample of Iranian patients. ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2016.08.026
更新日期:2016-10-15 00:00:00
abstract::Polychlorinated biphenyls (PCBs) activate neutrophils to induce degranulation and undergo superoxide production through a mechanism that involves stimulation of phospholipase A(2) (PLA(2)). Since the biochemical processes leading to the PCB-induced activation of this enzyme are unknown, the objective of this study was...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1999.8827
更新日期:2000-02-15 00:00:00