Abstract:
:Aminoglutethimide (AMG) is an aromatic amine aromatase inhibitor associated with a high incidence of idiosyncratic blood dyscrasias, especially agranulocytosis. Animal models of idiosyncratic drug reactions (IDRs) represent essential tools to study these reactions; however, there is currently no valid model of idiosyncratic drug-induced agranulocytosis. Although AMG does not cause agranulocytosis in most animals or humans, drugs associated with serious IDRs generally cause a higher incidence of mild reactions that resolve despite continued treatment. Therefore, the effects of AMG on neutrophils and bone marrow in rats were studied to understand the mechanisms of more serious IDRs. An increase in peripheral blood neutrophils occurred as early as 24 h after AMG treatment with minimal changes to the total leukocyte count. Further investigation using 5-bromo-2'-deoxyuridine (BrdU) found an increased release of neutrophils from the bone marrow. Histologically, this corresponded to an increase in myeloid cells in the bone marrow, which was confirmed by differential staining with CD45 and CD71. AMG treatment stimulated an increase in colony forming unit granulocyte-macrophage and colony forming unit granulocyte ex vivo. There was also a marked increase in the number of activated neutrophils in the circulation expressing the extravasation marker CD62L. These findings indicate that AMG affects neutrophil production, release, and function. Similar effects on neutrophil kinetics in clozapine-treated rats have previously been found, and transient neutrophilia has been observed in patients taking other drugs associated with idiosyncratic agranulocytosis; therefore, the changes observed with AMG may be biomarkers to predict the risk that a drug will cause agranulocytosis.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Ng W,Uetrecht Jdoi
10.1021/tx400224jsubject
Has Abstractpub_date
2013-08-19 00:00:00pages
1272-81issue
8eissn
0893-228Xissn
1520-5010journal_volume
26pub_type
杂志文章abstract::Arsenic is one of the inorganic pollutants typically found in natural waters, and its toxic effects on the human body are currently of great concern. For this reason, the search for detoxifying agents that can be used in a so-called "chelation therapy" is of primary importance. However, to the aim of finding the therm...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00506
更新日期:2020-04-20 00:00:00
abstract::4-Hydroxy-2-nonenal (HNE), a major electrophilic byproduct of lipid peroxidation, is mutagenic and cytotoxic. The two pairs of HNE-derived diastereomeric 1,N2-propanodeoxyguanosine 3'-monophosphate adducts were synthesized from reaction of HNE with 2'-deoxyguanosine 3'-monophosphate. After HPLC separation, these adduc...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx970100r
更新日期:1997-11-01 00:00:00
abstract::The hepatotoxicity of Troglitazone (TGZ) has been ascribed to the formation of reactive metabolites, and the primary reactive metabolite of TGZ has been confirmed to be an o-quinone methide. Oxidation of the chromane moiety is also known to produce quinone containing metabolites. Quantum chemical studies have been per...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200110h
更新日期:2011-07-18 00:00:00
abstract::1,2,3,4-Diepoxybutane (DEB) is a prominent carcinogenic metabolite of 1,3-butadiene (1,3-BD), an important industrial chemical and an environmental pollutant found in cigarette smoke and automobile exhaust. DEB is capable of inducing a variety of genotoxic effects, including point mutations, large deletions, and chrom...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0498206
更新日期:2004-12-01 00:00:00
abstract::Increasing exposure of biological systems to large amounts of polycyclic aromatic hydrocarbons is of great public concern. Organisms have an array of biological defense mechanisms, and it is believed that mucosal gel (which covers the respiratory system, the gastrointestinal tract, etc.) provides an effective chemical...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx100426s
更新日期:2011-03-21 00:00:00
abstract::Environmental stress induces the synthesis of glucose-regulated proteins (Grps) in the endoplasmic reticulum (ER) and heat shock proteins (Hsps) in the cytoplasm. Iodoacetamide (IDAM), a prototypical alkyating agent, induces both Grp and Hsp synthesis in renal epithelial cells and causes necrosis which is prevented by...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx990054q
更新日期:1999-10-01 00:00:00
abstract::Jay Amin hydroxamic acid (JAHA; N8-ferrocenylN1-hydroxy-octanediamide) is a ferrocene-containing analogue of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA). JAHA's cytotoxic activity on MDA-MB231 triple negative breast cancer (TNBC) cells at 72 h has been previously demonstrated with ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.7b00269
更新日期:2017-12-18 00:00:00
abstract::Aflatoxin Q1 8,9-oxide was synthesized and found to yield lower levels of N7-guanyl adducts than obtained from aflatoxin B1 8,9-oxide when mixed with calf thymus DNA or Salmonella typhimurium TA 98 cells. However, when S. typhimurium TA 98 was treated with the (analogous) epoxides of aflatoxin B1, aflatoxin G1, aflato...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00026a009
更新日期:1992-03-01 00:00:00
abstract::NADPH in microsomes reduces the hydroxocob(III)alamin form of vitamin B12 to cob(II)alamin and the supernucleophilic cob(I)alamin, which are both highly reactive toward xenobiotic epoxides formed by mammalian metabolism of dienes such as the industrially important chemicals chloroprene and 1,3-butadiene. With styrene,...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0497898
更新日期:2004-12-01 00:00:00
abstract::Marine toxins such as brevetoxins and ciguatoxins are produced by dinoflagellates and can accumulate in seafood. These toxins affect humans through seafood consumption. Intoxication is mainly characterized by gastrointestinal and neurological disorders and, in most severe cases, by cardiovascular problems. To prevent ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0342262
更新日期:2004-04-01 00:00:00
abstract::β-Lapachone (β-lap) is a promising antitumoral agent. DNA base oxidation and alkylation are among the expected damages by β-lap. Herein, we have explored the role that the homologous recombination pathway (HR), a critical DNA repair process in Saccharomyces cerevisiae, has in the cytotoxic profile of β-lap. We have fu...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx2004618
更新日期:2011-12-19 00:00:00
abstract::Raloxifene is a selective estrogen receptor modulator which is effective in the treatment of osteoporosis in postmenopausal women. We report herein that cytochrome P450 (P450)3A4 is inhibited by raloxifene in human liver microsomal incubations. The nature of the inhibition was irreversible and was NADPH- and preincuba...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0200109
更新日期:2002-07-01 00:00:00
abstract::Methylglyoxal is a mutagenic bis-electrophile that is produced endogenously from carbohydrate precursors. Methylglyoxal has been reported to induce DNA-protein cross-links (DPCs) in vitro and in cultured cells. Previous work suggests that these cross-links are formed between guanine and either lysine or cysteine side ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500068v
更新日期:2014-06-16 00:00:00
abstract::Acyl glucuronides (AGs) are reactive metabolites of carboxylic acid-containing drugs, which are associated with idiosyncratic toxicity (IDT) such as anaphylaxis, drug-induced liver injury, and so on. In this study, we developed a new in vitro approach for the quantitative assessment of the reactivity of AGs and their ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00111
更新日期:2019-10-21 00:00:00
abstract::The reactions of calf thymus DNA with four 1,3-dialkyl-3-acyltriazenes were studied alone or in the presence of pig liver esterase in pH 7.4 phosphate buffer for varying lengths of time. The best alkylating agent in the absence of esterase was determined to be 1,3-dimethyl-3-carbethoxytriazene (DMC), followed in order...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00028a013
更新日期:1992-07-01 00:00:00
abstract::Five major products (adducts A(1a), A(1b), A(2), A(3,) and B) from the reaction of guanosine (Guo) with 4-oxo-2(E)-nonenal (ONE) were detected by liquid chromatography-mass spectrometry (LC-MS). Tandem MS (MS/MS) analysis of these compounds suggested that modifications to the nucleoside had been introduced. Adducts A(...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0600189
更新日期:2006-06-01 00:00:00
abstract::Exposure to the tobacco-related nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine is carcinogenic to humans. Metabolic activation of NNK leads to the formation of DNA adducts, which play a critical role in NNK carcinogenesis. Adducts specific to NNK result from covalent linkag...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050028u
更新日期:2005-06-01 00:00:00
abstract::So far, there is limited information on biotransformation mechanisms and products of polar contaminants in freshwater crustaceans. In the present study, metabolites of biocides and pharmaceuticals formed in Gammarus pulex and Daphnia magna were identified using liquid chromatography-high resolution mass spectrometry. ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300457f
更新日期:2013-03-18 00:00:00
abstract::DNA conformational change and breakage induced by Cr(VI)-GSH interaction were characterized by the integrated tools of electrochemistry, atomic force microscopy (AFM), and DNA electrophoresis. While electrochemistry confirmed the formation of the active species generated from Cr(VI)-GSH reduction, which causes the DNA...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050134w
更新日期:2005-10-01 00:00:00
abstract::The toxicity of the ubiquitous pollutant and endogenous metabolite, acrolein, is due in part to covalent protein modifications. Acrolein reacts readily with protein nucleophiles via Michael addition and Schiff base formation. Potential acrolein targets in protein include the nucleophilic side chains of cysteine, histi...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800465m
更新日期:2009-04-01 00:00:00
abstract::Structure-function relationships for the inhibition of human cytochrome P450s (P450s) 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 flavonoid derivatives were studied. Thirty-two of the 33 flavonoids tested produced reverse type I binding spectra with P450 1B1, and the potencies of binding were correlated with the abilities to in...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx100286d
更新日期:2010-12-20 00:00:00
abstract::The toxicity of CuO nanoparticles (NPs) to human lung epithelial (A549) cells was investigated in this study. CuO NPs (10-100 mg/L) had significant toxicity to A549 cells, whereas CuO bulk particles (BPs) showed much lower toxicity (24 h IC(50), 58 and 15 mg/L for CuO BPs and NPs, respectively). Transmission electron ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx3002093
更新日期:2012-07-16 00:00:00
abstract::Inorganic arsenic is a strong carcinogen, possibly by interaction with the telomere length. The aim of the study was to evaluate how chronic arsenic exposure from drinking water as well as the arsenic metabolism efficiency affect the individual telomere length and the expression of telomere-related genes. Two hundred ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300222t
更新日期:2012-11-19 00:00:00
abstract::The toxic alpha,beta-unsaturated aldehyde acrolein readily attacks proteins, generating adducts at cysteine, histidine, and lysine residues. In this study, rabbit antiserum was raised against acrolein-modified keyhole limpet hemocyanin in the expectation that it would allow immunodetection of adducted proteins in biol...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0341106
更新日期:2003-10-01 00:00:00
abstract::Double-strand breaks are widely accepted to be the most toxic form of DNA damage. Molecules that produce double-strand breaks via a single chemical event are typically very cytotoxic and far less common than those that form single-strand breaks. It was recently reported that a commonly formed C4'-radical produces doub...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00032
更新日期:2015-04-20 00:00:00
abstract::It is vital that methylated trivalent arsenicals [MA(III) and DMA(III)] are described and characterized unequivocally due to their high toxicity. Two different ways of generating the methylated trivalent arsenicals have been practiced-reduction of the methylated pentavalent arsenical either by the sodium-metabisulfite...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx049978q
更新日期:2004-08-01 00:00:00
abstract::Previous studies suggested that lamotrigene (LTG) underwent bioactivation to a reactive aryl epoxide intermediate in rats. Nevertheless, definitive structures of these thioether conjugates, which are often needed to substantiate the mechanism of bioactivation and identity of reactive intermediate(s), were not fully es...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx9003243
更新日期:2010-01-01 00:00:00
abstract::Tetrandrine, a bisbenzylisoquinoline alkaloid, has demonstrated promising pharmacologic activities. The alkaloid has a great potential for clinical use, so a careful, thorough toxicity evaluation of the alkaloid is required. In the present study, 24 h acute toxicity of tetrandrine was evaluated in CD-1 mice. Single in...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200290s
更新日期:2011-12-19 00:00:00
abstract::The conformation of the crotonaldehyde-derived N(2)-[3-oxo-1(S)-methyl-propyl]-dG adduct in the oligodeoxynucleotide 5'-d(G(1)C(2)T(3)A(4)G(5)C(6)X(7)A(8)G(9)T(10)C(11)C(12))-3'.5'-d(G(13)G(14)A(15)C(16)T(17)C(18)G(19)C(20)T(21)A(22)G(23)C(2)(4))-3', where X = N(2)-[3-oxo-1(S)-methyl-propyl]-dG, is reported. This addu...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0600604
更新日期:2006-08-01 00:00:00
abstract::In vitro techniques have been utilized to investigate the microsomal enzymes involved in the metabolism of lauric acid and to establish conditions in which it can be used as a model substrate for both cytochrome P450 4A and cytochrome P450 2E1 in human liver microsomes. Studies of enzyme kinetics of lauric acid omega-...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00042a018
更新日期:1994-11-01 00:00:00