Abstract：
:Drug hypersensitivity reactions adversely affect treatment outcome, increase the length of patients' hospitalization, and limit the prescription options available to physicians. In addition, late stage drug attrition and the withdrawal of licensed drugs cost the pharmaceutical industry billions of dollars. This significantly increases the overall cost of drug development and by extension the price of licensed drugs. Drug hypersensitivity reactions are characterized by a delayed onset, and reactions tend to be more serious upon re-exposure. The role of drug-specific T-cells in the pathogenesis of drug hypersensitivity reactions and definition of the nature of the binding interaction of drugs with HLA and T-cell receptors continues to be the focus of intensive research, primarily because susceptibility is associated with expression of one or a small number of HLA alleles. This review critically examines the mechanisms of T-cell activation by drugs. Specific examples of drugs that activate T-cells via the hapten, the pharmacological interaction with immune receptors and the altered self-peptide repertoire pathways, are discussed. Furthermore, the impacts of drug metabolism, drug-protein adduct formation, and immune regulation on the development of drug antigen-responsive T-cells are highlighted. The knowledge gained from understanding the pathways of T-cell activation and susceptibility factors for drug hypersensitivity will provide the building blocks for the development of predictive in vitro assays that will prevent or help to minimize the incidence of these reactions in clinic.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Hammond S,Thomson PJ,Ogese MO,Naisbitt DJdoi
10.1021/acs.chemrestox.9b00327subject
Has Abstractpub_date
2020-01-21 00:00:00pages
77-94issue
1eissn
0893-228Xissn
1520-5010journal_volume
33pub_type
杂志文章,评审abstract：:Thiosemicarbazones derived from acetylpyrazines were prepared by condensing an acetylpyrazine or a ring-substituted acetylpyrazine with thiosemicarbazide. Using the same procedure, N, N-dimethylthiosemicarbazones were synthesized from acetylpyrazines and N, N-dimethylthiosemicarbazide. A total of 20 compounds (16 nove...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx800182k
更新日期：2008-09-01 00:00:00
abstract：:Docosahexaenoic acid (DHA) is a semiessential polyunsaturated fatty acid (PUFA) for eukaryotic cells that is found in natural sources such as fish and algal oils and widely used as an ingredient for omega-3 containing foods or supplements. DHA effects are connected to its natural structure with six cis double bonds, b...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.8b00021
更新日期：2018-03-19 00:00:00
abstract：:3-Methylindole (3MI) is a preferential pneumotoxicant found in cigarette smoke. A number of lung-expressed human cytochrome P450 enzymes, including 1A1, 2F1, and 2A13, catalyze the metabolism of 3MI to reactive intermediates that fragment DNA, measured with the Comet assay to assess DNA damage, in a cytochrome P450-de...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx100147z
更新日期：2010-11-15 00:00:00
abstract：:Carcinogens induce complex transcriptional responses in cells that may hold key mechanistic information. Benzo(a)pyrene (BaP) modulation of transcription may occur through the activation of the aryl hydrocarbon receptor (AHR) or through responses to DNA damage. To characterize further the expression profiles induced b...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx700252n
更新日期：2007-12-01 00:00:00
abstract：:The effect of trans-1,2-dichloroethylene (DCE), an inhibitor of cytochrome P450 (P450) 2E1, on the catalytic activities and total content of hepatic P450 was determined in vivo and in vitro. Hepatic microsomes were prepared from groups of rats prior to dosing and at 2, 5, 12, and 24 h postdosing, and total P450 conten...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx970227g
更新日期：1998-07-01 00:00:00
abstract：:1-{4-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]benzyl}azetidine-3-carboxylic acid (MRL-A) is a potent sphingosine-1-phosphate-1 receptor agonist, with potential application as an immunosuppressant in organ transplantation or for the treatment of autoimmune diseases. When administered orally to rats, radiolabeled ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx300017s
更新日期：2012-07-16 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：:Prodrugs of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) are promising anticancer agents. The 90CE moiety is a readily latentiated, short-lived (t1/2 ∼ 30 s) chloroethylating agent that can generate high yields of oxophilic electrophiles responsible for the chloroethylation of the O-6 position of guanine ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx500197t
更新日期：2014-08-18 00:00:00
abstract：:Nitroaromatic compounds represent a major class of industrial chemicals that are also found in nature. Polycyclic derivatives are regarded as potent mutagens and carcinogens following bioactivation to produce nitrenium electrophiles that covalently modify DNA to afford N-linked C8-2'-deoxyguanosine (C8-dG) lesions tha...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.9b00411
更新日期：2020-02-17 00:00:00
abstract：:Chromium(III) tris(picolinate) [Cr(pic)3] is currently a very popular nutritional supplement; however, its safety has recently been questioned, especially with regard to its ability to act as a clastogen. At physiologically relevant concentrations, Cr(pic)3 is reduced by biological reductants, including ascorbate and ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx9900167
更新日期：1999-06-01 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：:2-(Glutathion-S-yl)-1,4-benzoquinone was found to be remarkably unstable in phosphate buffer (pH 7.4) even in the absence of oxygen. Intramolecular addition of the alpha-amino group of the glutamate residue to the quinone ring yielded ultimately 2,3-(glutathion-N, S-yl)-1,4-benzoquinone and 2,6-(glutathion-N,S-yl)-1,4...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx9800699
更新日期：1998-10-01 00:00:00
abstract：:Thioureas are oxygenated by flavin-containing monooxygenases (FMOs), forming reactive sulfenic and/or sulfinic acids. Sulfenic acids can reversibly react with GSH and drive oxidative stress through a redox cycle. For this reason, thiourea S-oxygenation is an example of FMO-dependent bioactivation of a xenobiotic. Func...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx034253s
更新日期：2004-05-01 00:00:00
abstract：:Among the cellular components that can react directly with peroxynitrite in the presence of physiological CO(2) concentrations are sulfur-, selenium-, and metal-containing proteins, in particular hemoproteins. We have previously shown that the reactions of peroxynitrite with oxymyoglobin (MbFeO(2)) and oxyhemoglobin p...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx025595l
更新日期：2003-03-01 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：:Cytochrome P450 enzymes (CYPs) metabolize alkyl- and arylamines, generating several different products. For the primary and secondary amines, some of these reactions result in hydroxylated amines, which may be toxic. Thus, when designing new drugs containing amine groups, it is important to be able to predict if a giv...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx500371a
更新日期：2015-04-20 00:00:00
abstract：:The reaction of the antitumor agent leinamycin with thiols converts this natural product into an episulfonium ion that alkylates the N7-position of guanine residues in double-stranded DNA. It is reported here that depurination of this adduct is unusually facile, occurring with a half-life of about 3.5 h at pH 7 and 37...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx049964k
更新日期：2004-07-01 00:00:00
abstract：:Proton pump inhibitors (PPIs) are extensively used for the treatment of gastric acid-related disorders. PPIs appear to be well tolerated and almost have no short-term side effects. However, the clinical adverse reactions of long-term PPI usage are increasingly reported in recent years. So far, there is no study that e...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx5003782
更新日期：2015-03-16 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：:Nucleotide excision repair (NER) removes lesions caused by environmental mutagens or UV light from DNA. A hallmark of NER is the extraordinarily wide substrate specificity, raising the question of how one set of proteins is able to recognize structurally diverse lesions. Two key features of good NER substrates are tha...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx3003033
更新日期：2012-11-19 00:00:00
abstract：:The tremendous demand of the market for carbon nanotubes has led to their massive production that presents an increasing risk through occupational exposure. Lung deposition of carbon nanotubes is known to cause acute localized pulmonary adverse effects. However, systemic cardiovascular damages associated with acute pu...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx5004003
更新日期：2015-03-16 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：:A freely available Windows-based program, RNSim1A, is utilized to predict metal-independent reactive nitrogen species (RNS) chemistry (oxidation, nitrosation, and nitration) under simulated biological conditions and make the following specific predictions. (1) The peak in oxidative reactions that occurs in vitro with ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx060061w
更新日期：2006-09-01 00:00:00
abstract：:Butadiene monoxide, a toxic metabolite of 1,3-butadiene, is a substrate for the human placental glutathione (GSH) S-transferase. The products have been identified as S-(2-hydroxy-3-buten-1-yl)glutathione (I) and S-(1-hydroxy-3-buten-2-yl)glutathione (II). S-(4-hydroxy-2-buten-1-yl)glutathione (III), which was formed c...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00022a006
更新日期：1991-07-01 00:00:00
abstract：:Vinyl chloride and acrolein are important industrial chemicals. Both form DNA adducts, vinyl chloride after enzymatic oxidation to chlorooxirane and acrolein by direct reaction. Reaction at the N(2) position of guanine is a major pathway. The resulting 2-oxoethyl and 3-oxopropyl adducts cyclize spontaneously to hydrox...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx990167+
更新日期：2000-05-01 00:00:00
abstract：:Divinyl sulfone (DVS) is an important oxidative metabolic product of sulfur mustard (SM) in vitro and in vivo. Although DVS is not a classical blister agent, its high reactivity and toxicity induced by vinyl groups can also cause blisters like SM upon contact with the skin, eyes, and respiratory organs. The purpose of...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.7b00196
更新日期：2017-10-16 00:00:00
abstract：:Carcinogenic polycyclic aromatic hydrocarbons (PAH), e.g., benzo[a]pyrene (BaP), possess a bay region comprising an ortho-fused benzene ring. Benzo[ghi]perylene (BghiP) represents the group of PAHs lacking such a "classic" bay region and hence cannot be metabolically converted like BaP to bay region dihydrodiol epoxid...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx049698a
更新日期：2005-04-01 00:00:00
abstract：:There is considerable evidence for the exposure of humans to an unknown ethylating agent, and some studies indicate that cigarette smoking may be one source of this exposure. Therefore, we have developed a liquid chromatography-nanoelectrospray-high resolution tandem mass spectrometry-selected reaction monitoring (LC-...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx200262d
更新日期：2011-10-17 00:00:00
abstract：:Four novel cadmium-chelating agents N,N'di(D-glucosyl)alkanediamine-N,N'-bis(carbodithioates) 4a-e were prepared as disodium salts of the general formula (CH2)n[N(CS2Na)CH2(CHOH)4CH2OH]2, where n = 7, 8, 10, and 12. They were synthesized by the reductive coupling of 2 mol of alpha-D-(+)-glucose (1) with 1 mol of the c...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx950123a
更新日期：1996-01-01 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
