Abstract:
:Valproic acid (VPA) and the unsaturated metabolites, 2-ene VPA and (E)-2,(Z)-3'-diene VPA, demonstrated dose-dependent cytotoxicity in primary cultures of rat hepatocytes, as evaluated by lactate dehydrogenase (LDH) leakage. Cellular glutathione (GSH) was depleted by adding buthionine sulfoximine (BSO) to the culture medium. Induction of cytochrome P450 by pretreatment of rats with phenobarbital or pregnenolone-16 alpha-carbonitrile enhanced the cytotoxicity of parent VPA in BSO-treated hepatocytes. The cytotoxicity of 4-ene VPA was apparent in BSO-treated hepatocytes with detectable loss of cell viability at 1 microM of added 4-ene VPA. Depletion of cellular GSH also increased the cytotoxicities of 2-ene VPA and (E)-2,(Z)-3'-diene VPA. The cytotoxicity of 2-ene VPA was comparable to or higher than that of VPA, producing loss of viability at concentrations > or = 5 mM. Time-course evaluation of hepatocyte response to 4-ene VPA in the GSH-depleted state revealed a delayed cytotoxicity with no effect during the first 12 h of exposure followed by a pronounced toxicity between 12 and 14 h. Two major GSH conjugates of 4-ene VPA metabolites, namely 5-GS-4-hydroxy VPA lactone and 5-GS-3-ene VPA, were detected in 4-ene VPA treated hepatocytes. Consistent with this finding, a 50% decrease in cellular GSH levels was observed following 4-ene VPA treatment. Under similar conditions, neither toxicity nor the GSH conjugated metabolite were detected in cells treated with the alpha-fluorinated 4-ene VPA analogue (alpha-F-4-ene VPA). The antioxidants, vitamin C and vitamin E, demonstrated a cytoprotective effect against 4-ene VPA-induced injury in GSH-depleted hepatocytes. These results are in support of hepatocellular bioactivation of VPA via 4-ene VPA to highly reactive species, which are detoxified by GSH. The susceptibility of hepatocytes to VPA metabolite-mediated cytotoxicity depends on cellular GSH homeostasis.
journal_name
Toxicologyjournal_title
Toxicologyauthors
Jurima-Romet M,Abbott FS,Tang W,Huang HS,Whitehouse LWdoi
10.1016/0300-483x(96)03352-5subject
Has Abstractpub_date
1996-08-01 00:00:00pages
69-85issue
1eissn
0300-483Xissn
1879-3185pii
0300483X96033525journal_volume
112pub_type
杂志文章相关文献
TOXICOLOGY文献大全abstract::The present study investigates the influence of different levels of Schistosoma mansoni infection (60, 120, 180, 300, 600 cercariae per mice) after 33 days on the activity of aryl hydrocarbon hydroxylase (AHH) and the formation of hepatic hydrogen peroxide (H(2)O(2)) during the metabolic activation of benzo(a)pyrene [...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/s0300-483x(01)00372-9
更新日期:2001-06-21 00:00:00
abstract::Troglitazone is a thiazolidinedione antidiabetic agent with insulin-sensitizing activities that was withdrawn from the market in 2000 due to its association with idiosyncratic hepatotoxicity. To address the suspected autoantibody production associated with troglitazone, we investigated autoantibodies in sera from pati...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/j.tox.2005.07.012
更新日期:2005-12-01 00:00:00
abstract::Dietary exposure to vomitoxin (VT) results in hyperelevated serum IgA and IgA nephropathy in mice. To assess the possible role of cytokines in this IgA dysregulation, the effects of a single oral exposure in B6C3F1 male mice to 0, 5 or 25 mg/kg BW VT on production of IgA and cytokines in Peyer's patch (PP) and spleen ...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/s0300-483x(97)00087-5
更新日期:1997-09-26 00:00:00
abstract::Studies on the pulmonary retention of benzo[a]pyrene after inhalation have shown that clearance is biphasic, with one component clearing with a half-time greater than 1 day and another with a half-time less than 1 day. In the work reported here we demonstrated that the amount of benzo[a]pyrene instilled in the lungs c...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/0300-483x(85)90066-6
更新日期:1985-06-28 00:00:00
abstract::The standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes is not sufficiently effective against all types of nerve agents. Alternative therapeutic strategies are required and bispyridinium non-oximes, acting as nicotinic antagonists, were identified as promising compounds. A pr...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/j.tox.2012.02.002
更新日期:2012-04-11 00:00:00
abstract::Mitochondria play a central role in the life and death of cells. These organelles serve as the major energy-producing power-house, whereby the generation of ATP is associated with the utilization of molecular oxygen. A significant fraction (2-3%) of molecular oxygen consumed by mitochondria may be reduced in a one-ele...
journal_title:Toxicology
pub_type: 杂志文章,评审
doi:10.1016/j.tox.2004.11.027
更新日期:2005-03-15 00:00:00
abstract::Although the need for non-animal alternatives has been well recognised for the human health hazard assessment of chemicals in general, it has become especially pressing for cosmetic ingredients due to the full implementation of testing and marketing bans on animal testing under the European Cosmetics Regulation. This ...
journal_title:Toxicology
pub_type:
doi:10.1016/j.tox.2020.152421
更新日期:2020-04-30 00:00:00
abstract::Antidepressants are generally used for treatment of various mood and anxiety disorders. Several studies have shown the anti-tumor and cytotoxic activities of some antidepressants, but the underlying mechanisms were unclear. Maprotiline is a tetracyclic antidepressant and possesses a highly selective norepinephrine reu...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/j.tox.2012.11.013
更新日期:2013-02-08 00:00:00
abstract::Solar radiation induces acute and chronic reactions in human and animal skin. Chronic repeated exposures are the primary cause of benign and malignant skin tumors, including malignant melanoma. Among types of solar radiation, ultraviolet B (290-320 nm) radiation is highly mutagenic and carcinogenic in animal experimen...
journal_title:Toxicology
pub_type: 杂志文章,评审
doi:10.1016/s0300-483x(03)00150-1
更新日期:2003-07-15 00:00:00
abstract::The intravenous LD50 of cefuroxime sodium for mice was 10.4 g/kg. The maximum dosage administered in other acute toxicity tests was well tolerated by mice (10 g/kg, subcutaneous), by rats (4 g/kg, intravenous, 5 g/kg, subcutaneous) and by cats, dogs and monkeys (2 g/kg, intramuscularly). Cefuroxime sodium was administ...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/s0300-483x(79)80003-7
更新日期:1979-05-01 00:00:00
abstract::Chronic treatment of BALB and GRS mice with BHT (2,6-di-tert-butyl-4-methylphenol) following a single urethane injection increases lung tumor multiplicity, but this does not occur in CXB4 mice. Previous data suggest that promotion requires the conversion of BHT to a tert-butyl-hydroxylated metabolite (BHTOH) in lung a...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/s0300-483x(00)00449-2
更新日期:2001-03-07 00:00:00
abstract::The safety of an açai (Euterpe oleracea Mart.) pulp enriched fruit and berry juice, MonaVie Active®, fortified with the functional ingredient, glucosamine, was studied. The beverage was found not to be mutagenic, clastogenic, cytotoxic, or genotoxic, as determined by the bacterial reverse mutation assay, chromosomal a...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/j.tox.2010.04.017
更新日期:2010-11-28 00:00:00
abstract::p-Chloro-m-cresol (PCMC) and p-chloro-m-xylenol (PCMX) are known to cause allergic contact dermatitis. For risk assessment of skin sensitizers, information on dose-response profiles in the induction and elicitation phases and cross-reactivity with analogous chemicals are important. In the non-radioactive local lymph-n...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/s0300-483x(03)00161-6
更新日期:2003-08-28 00:00:00
abstract::Drug-induced hepatotoxicity is a major problem in drug development, and oxidative stress is known as one of the causes. Superoxide dismutases (SODs) are important antioxidant enzymes against reactive oxygen species (ROS). Mitochondria are the major source of superoxide production, and SOD2 is mainly localized in mitoc...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/j.tox.2009.07.017
更新日期:2009-10-01 00:00:00
abstract::Several inhibitors of cytochrome P-450 mediated oxidative transformations, ethyl 2-diethylaminoethyl-2-phenyl-2-ethylmalonate, ethyl-2-diethyl-aminoethyl-2-ethyl-2-buthylmalonate, 2,4 dichloro-6-phenoxyethyl diethylamine, 2-diethylaminoethyl-2-phenyl- (2-propene)-4-penten-1-oate or 3-amino,1,2,4 triazole were not able...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/0300-483x(80)90117-1
更新日期:1980-01-01 00:00:00
abstract::Increasing experimental and clinical evidence suggest a contribution of non-drug related risk factors (e.g., underlying disease, bacterial/viral infection) to idiosyncratic drug reactions (IDR). Our previous work showed that co-treatment with bacterial endotoxin (LPS) and therapeutic doses of diclofenac (Dcl), an anal...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/j.tox.2015.03.004
更新日期:2015-05-04 00:00:00
abstract::Rats received 0, 200, 1000 and 5000 ppm metaldehyde in the diet for 2 years. Reproduction studies over three generations using the same dietary levels were carried out. In the third litter of each generation attention was paid to possible embryotoxic or teratogenic effects. The parameters studied included growth, food...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/0300-483x(75)90026-8
更新日期:1975-01-01 00:00:00
abstract::Rats were treated for 4 weeks with chlorphentermine hydrochloride (30 mg/kg, i.p., 5 days/seek), a regimen which causes a profound phospholipidosis in the alveolar macrophages (AMs). The susceptibility of these lipid-laden cells to lipid peroxidation was examined and compared to AMs from control (untreated) rats. Lipi...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/0300-483x(80)90078-5
更新日期:1980-01-01 00:00:00
abstract::Spores of actinomycetes, mesophilic gram-positive bacteria, isolated from moldy houses, induced the expression of inducible NO-synthase (iNOS) with a subsequent NO-production in RAW264.7 macrophages. No differences were detected between production of nitric oxide (NO) by alive or irradiated spores of different strains...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/s0300-483x(97)00141-8
更新日期:1997-12-26 00:00:00
abstract::The effects of isoflurane, 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether, on the oxidative metabolism of halothane to produce trifluoroacetic acid (TFA) and on the reductive metabolism of halothane to produce chlorodifluoroethylene (CDE) and chlorotrifluoroethane (CTE) in liver microsomes of guinea pig were exami...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/0300-483x(95)03154-8
更新日期:1995-12-15 00:00:00
abstract::The cytochrome P-450 enzymes are responsible for the oxidation of xenobiotic chemicals including drugs, pesticides, and carcinogens. These enzymes include cytochrome P450, cytochrome b(5), arylhydrocarbon (benzo[a]pyrene) hydroxylase (AHH), NADPH-cytochrome C reductase and dimethylnitrosamine N-demethylase I (DMN-dI)....
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/s0300-483x(01)00473-5
更新日期:2001-12-14 00:00:00
abstract::The effects of lindane on alpha-aminoisobutyric acid and uridine uptake were studied in the rat line C-6 of glial origin. Different levels of modifications could be distinguished by use of 2 modes of investigation. One study, carried out within minutes of contact with lindane, has shown that the inhibition of alpha-am...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/0300-483x(80)90103-1
更新日期:1980-01-01 00:00:00
abstract::Bisphenol A (BPA) is a commonly used endocrine-disrupting chemical used as a component of polycarbonates plastics that has potential adverse effects on human health. Exposure to BPA during development has been implicated in memory deficits, but the mechanism of action underlying the effect is not fully understood. In ...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/j.tox.2016.01.010
更新日期:2016-02-03 00:00:00
abstract::The objective of this study was to establish a hypospadiac rat model by maternal exposure to di-n-butyl phthalate (DBP) and to evaluate the developmental abnormalities of hypospadiac male rats. Timed-pregnant rats were given DBP by gastric intubation at doses of 0, 250, 500, 750 or 1000 mg/kg body weight (bw)/day from...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/j.tox.2007.01.018
更新日期:2007-04-11 00:00:00
abstract::Amiodarone is a class III anti-arrhythmic compound that is iodinated, cationic and amphiphilic in nature. The clinical use of amiodarone may be associated with various side-effects, including pulmonary and hepatic toxicity. Use of this compound during pregnancy may therefore place the fetus at risk through in utero ex...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/0300-483x(91)90085-f
更新日期:1991-01-01 00:00:00
abstract::The rodent Hershberger assay has been used predominantly by the pharmaceutical industry to evaluate androgenic and antiandrogenic chemicals for potential therapeutic use. However, this assay has not yet been formally validated and standardized for use in toxicology testing. There are many variations in the protocol us...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/s0300-483x(01)00361-4
更新日期:2001-05-11 00:00:00
abstract::An in vitro model of the rat nasal cavity has been used to compare the responses of nasal tissues in vitro, using loss of intracellular ATP and potassium as indices of toxicity, with the pathological changes occurring following in vivo exposure to four test compounds. Turbinates were incubated in vitro with the test c...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/s0300-483x(99)00180-8
更新日期:2000-04-07 00:00:00
abstract::Glutathione S-transferases and glutathione play an important role in the detoxification of most toxic agents. In the present study, the protective effects of some antioxidants (L-ascorbic acid (AA), vitamin E (VE) or garlic) on carbon tetrachloride-induced changes in the activity of alanine amino transferase (ALT), as...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/s0300-483x(01)00429-2
更新日期:2001-08-28 00:00:00
abstract::(1) Following the administration of the highly toxic agent 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to pregnant mice, exceedingly low concentrations of this substance were found in the embryo and fetus between gestational days 11 and 18 (between 0.04 and 0.14% of the maternal dose/g tissue). (2) Tissue levels of tCD...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/0300-483x(81)90037-8
更新日期:1981-01-01 00:00:00
abstract::The mouse lymphoma thymidine kinase assay (MLA) has been optimized to quantitatively determine the in vitro mutagenicity of cigarette mainstream smoke particulate phase. To test whether the MLA is able to discriminate between different cigarette types, specially constructed cigarettes each containing a single tobacco ...
journal_title:Toxicology
pub_type: 杂志文章
doi:10.1016/j.tox.2006.07.019
更新日期:2006-10-29 00:00:00