Abstract:
:Oxidation of the tris(p-carboxyltetrathiaaryl)methyl (TAM) EPR radical probe, TAMa(•), by rat liver microsomes (RLM) + NADPH, or horseradish peroxidase (HRP) + H2O2, or K2IrCl6, led to an intermediate cation, TAMa(+), which was treated with glutathione (GSH), with formation of an adduct, TAMa-SG(•), resulting from the substitution of a TAMa(•) carboxylate group with the SG group. L-α-Amino acids containing a strong nucleophilic residue (NuH), such as L-cysteine or L-histidine, also reacted with TAMa(+), with formation of radical adducts TAMa-Nu(•) in which a carboxylate group of TAMa(•) was replaced with Nu. Other less nucleophilic L-α-amino acids, such as L-arginine, L-serine, L-threonine, L-tyrosine, or L-aspartate, as well as the tetrapeptide H-(Gly)4-OH, reacted with TAMa(+) via their α-NH2 group, with formation of an iminoquinone methide, IQMa, deriving from an oxidative decarboxylation and amination of TAMa(•). Upon reaction of TAMa(+) with L-proline and L-lysine, N-substituted iminoquinone methide adducts, IQMa-Pro and IQMa-Lys, were formed. Finally, preliminary results showed that oxidation of TAMa(•) in the presence of bovine serum albumin (BSA), led to the covalent binding of TAMa-derived metabolites to BSA. Oxidation of another frequently used TAM probe, TAMb(•) (Oxo63), in the presence of GSH, N-acetyl-cysteine methyl ester, or histidine also led to TAMb-Nu(•) adducts equivalent to the corresponding TAMa-Nu(•) adducts, suggesting that the oxidative metabolism of such TAM(•) probes could lead to protein covalent binding. Moreover, the above data describe an easy access to new TAM radical EPR probes coupled to amino acids, peptides or proteins that could be useful for addressing various biological targets.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Decroos C,Boucher JL,Mansuy D,Xu-Li Ydoi
10.1021/tx400467psubject
Has Abstractpub_date
2014-04-21 00:00:00pages
627-36issue
4eissn
0893-228Xissn
1520-5010journal_volume
27pub_type
杂志文章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::Hydrophobic and volatile chemicals have proven to be difficult to dose in cell assays. Cosolvents are often needed to dissolve these chemicals in cell culture medium. Moreover, the free concentration of these chemicals in culture medium may diminish over time due to metabolism, evaporation, and nonspecific binding to ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx1002595
更新日期:2010-11-15 00:00:00
abstract::Pentachlorophenol (PCP) was shown to function as a reducing substrate for horseradish peroxidase (HRP) and to stimulate the HRP-catalyzed reduction of 5-phenyl-4-penten-1-yl hydroperoxide (PPHP) to 5-phenyl-4-penten-1-ol. HRP catalyzed the hydroperoxide-dependent oxidation of PCP, using H2O2, PPHP, or ethyl hydroperox...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00045a005
更新日期:1995-04-01 00:00:00
abstract::Lapatinib (LAP), an oral tyrosine kinase inhibitor for the treatment of metastatic breast cancer, has been associated with idiosyncractic hepatotoxicity. Recent investigations have implicated the importance of P450 3A4/5 enzymes in the formation of an electrophilic quinone imine (LAPQI) metabolite generated through fu...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00524
更新日期:2016-05-16 00:00:00
abstract::Chemically reactive species formed from the metabolism of carboxylic acid-containing compounds have been proposed as mediators of their toxic side-effects. Two alternative metabolic pathways known to be involved in the generation of reactive acylating metabolites of carboxylic acids are acyl glucuronidation and acyl-C...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx020013l
更新日期:2002-10-01 00:00:00
abstract::Lumiracoxib (Prexige; 2-[(2-fluoro-6-chlorophenyl)amino]-5-methyl-benzeneacetic acid) is a cyclooxygenase-2 selective inhibitor for the symptomatic treatment of osteoarthritis. Recently, the drug has been withdrawn in several countries due to serious liver side effects. Li et al. recently have shown that lumiracoxib i...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx8002356
更新日期:2009-01-01 00:00:00
abstract::Senescence, which is irreversible cell cycle arrest, is induced by various types of DNA damage, including genotoxic stress. Senescent cells show dysregulation of tumor suppressor genes and other regulators of cellular proliferation. Activating transcription factor 3 (ATF3) plays a pleiotropic role in biological proces...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500341z
更新日期:2015-01-20 00:00:00
abstract::Divicine is an unstable aglycon metabolite of the fava bean pyrimidine beta-glucoside vicine. Divicine has long been thought to be a mediator of an acute hemolytic crisis, known as favism, in susceptible individuals who ingest fava beans (Vicia faba). However, a recent report has questioned the chemical identity of th...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00034a009
更新日期:1993-07-01 00:00:00
abstract::Formyl chloride has been indirectly implicated as an intermediate in the oxidation of CH(2)Cl(2) and proposed to be a product of the oxidation of some other compounds. Formyl chloride was synthesized and added to aqueous solutions, with CO formed as a product. The presence of glutathione (GSH) did not reduce the yield...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx060087n
更新日期:2006-08-01 00:00:00
abstract::A transient energy impairment with resultant release and subsequent reuptake of 5-hydroxytryptamine (5-HT) and NMDA receptor activation with consequent cytoplasmic superoxide (O(2)(-)(*)), nitric oxide (NO(*)), and peroxynitrite (ONOO(-)) generation have all been implicated in a neurotoxic cascade which ultimately lea...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx020029b
更新日期:2002-10-01 00:00:00
abstract::The DNA alkylating mechanism of PNU-159682 (PNU), a highly potent metabolite of the anthracycline nemorubicin, was investigated by gel-electrophoretic, HPLC-UV, and micro-HPLC/mass spectrometry (MS) measurements. PNU quickly reacted with double-stranded oligonucleotides, but not with single-stranded sequences, to form...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.6b00362
更新日期:2017-02-20 00:00:00
abstract::Oxidative stress is a contributing factor in a number of chronic diseases, including cancer, atherosclerosis, and neurodegenerative diseases. Lipid peroxidation that occurs during periods of oxidative stress results in the formation of lipid electrophiles, which can modify a multitude of proteins in the cell. 4-Hydrox...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00485
更新日期:2016-03-21 00:00:00
abstract::Kinetic simulation can help obtain deeper insight into the molecular mechanisms of complex processes, such as lipid peroxidation (LPO) in low-density lipoprotein (LDL). We have previously set up a single-compartment model of this process, initiating with radicals generated externally at a constant rate to show the int...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx9700073
更新日期:1997-06-01 00:00:00
abstract::Antineoplastic therapy with anthracyclines like doxorubicin (DOX) and daunorubicin (DNR) is limited by the possible development of a dose-related cardiomyopathy. Secondary alcohol metabolites like doxorubicinol (DOXol) and daunorubicinol (DNRol), formed by cytoplasmic two-electron reductases, have been implicated as p...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx060159a
更新日期:2006-11-01 00:00:00
abstract::We report on the generation of computer-based models for the prediction of the chromosome-damaging potential of chemicals as assessed in the in vitro chromosome aberration (CA) test. On the basis of publicly available CA-test results of more than 650 chemical substances, half of which are drug-like compounds, we gener...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx060136w
更新日期:2006-10-01 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::Understanding the molecular basis of inorganic chemical toxicity has lagged behind the proliferation of detailed mechanisms that explain the biochemical toxicology of many organic xenobiotics. In this perspective, general barriers to explicating the bioinorganic chemistry of toxic metals are considered, followed by a ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.6b00328
更新日期:2017-01-17 00:00:00
abstract::There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to myriad adverse health effects, including cancer of the bladder. We set out to identify DNA methylation patterns associated with arsenic and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from t...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500393y
更新日期:2015-06-15 00:00:00
abstract::The importance of adsorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis is expected to grow substantially due to recent failures in detecting severe toxicity issues of new chemical entities during preclinical/clinical development. Traditionally, safety risk assessment studies for humans have b...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00364
更新日期:2020-01-21 00:00:00
abstract::Coumadin (R/S-warfarin) anticoagulant therapy poses a risk to over 50 million Americans, in part due to interpersonal variation in drug metabolism. Consequently, it is important to understand how metabolic capacity is influenced among patients. Cytochrome P450s (P450 or CYP for a specific isoform) catalyze the first m...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx1000283
更新日期:2010-05-17 00:00:00
abstract::The rat esophagus is strikingly sensitive to tumor induction by nitrosamines, and it has been hypothesized that this tissue contains cytochrome P450 enzymes (P450s) which catalyze the metabolic activation of these carcinogens. The metabolic capacity of the esophagus is not well characterized. In the study described he...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx010065v
更新日期:2001-10-01 00:00:00
abstract::Concerns have been raised that diacetyl (DA) might be a respiratory sensitizer based on its LUMO energy similar to that of the respiratory allergen toluene-2,4-diisocyanate (TDI) and results of a local lymph node assay (LLNA) that reported an EC3 of 1.9%. To better understand the concerns, we performed a systematic li...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx400097v
更新日期:2013-05-20 00:00:00
abstract::Exposure of proteins to radicals in the presence of O(2) brings about multiple changes in the target molecules. These alterations include oxidation of side chains, fragmentation, cross-linking, changes in hydrophobicity and conformation, altered susceptibility to proteolytic enzymes, and formation of new reactive grou...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0001171
更新日期:2000-11-01 00:00:00
abstract::Benzo[a]pyrene diol epoxides (BPDEs) are the ultimate carcinogenic species of benzo[a]pyrene, a prototype polycyclic aromatic hydrocarbon (PAH). BPDE-modified DNA duplexes can adopt multiple conformations depending on the nature of the modified bases, the stereochemistry at the location of the covalent linkage, and th...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050308+
更新日期:2006-02-01 00:00:00
abstract::The Adverse Outcome Pathway (AOP) paradigm details the existing knowledge that links the initial interaction between a chemical and a biological system, termed the molecular initiating event (MIE), through a series of intermediate events, to an adverse effect. An important example of a well-defined MIE is the formatio...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.6b00099
更新日期:2016-06-20 00:00:00
abstract::Sudoxicam and meloxicam are nonsteroidal anti-inflammatory drugs (NSAIDs) from the enol-carboxamide class. While the only structural difference between the two NSAIDs is the presence of a methyl group on the C5-position of the 2-carboxamidothiazole motif in meloxicam, a marked difference in their toxicological profile...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800185b
更新日期:2008-09-01 00:00:00
abstract::Although selective estrogen receptor modulators (SERMs) are useful in the treatment and prevention of breast cancer, the SERM tamoxifen has been associated with an increased risk of endometrial cancer possibly due to metabolism to electrophilic quinoids. Another SERM, arzoxifene is currently in clinical trials for the...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx049776u
更新日期:2005-02-01 00:00:00
abstract::Furanoid 8-epidiosbulbin E acetate (EEA) is one of the most abundant diterpenoid lactones in herbal medicine Dioscorea bulbifera L. (DB). Our early work proved that EEA could be metabolized to EEA-derived cis-enedial (EDE), a reactive intermediate, which is required for the hepatotoxicity observed in experimental anim...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00016
更新日期:2020-07-20 00:00:00
abstract::2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 1-nitropyrene (1-NP), and benzo[a]pyrene (BaP) are toxic environmental pollutants. TCDD was shown to suppress p53 expression in response to genotoxic stress and hypoxic conditions. However, the mechanism of TCDD's actions is not clearly understood. Our data showed that pretr...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200309p
更新日期:2011-12-19 00:00:00
abstract::Two hemorrhagic proteases, Lachesis hemorrhagic toxins a and b (LHTa and LHTb), were isolated from the venom of Lachesis muta, which is distributed in Central and South America. One protease showed strong hemorrhagic action, while the other showed weak hemorrhagic activity even though the two enzymes are very similar ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00006a003
更新日期:1988-11-01 00:00:00