Abstract:
:The process of disinfecting drinking water inadvertently leads to the formation of numerous disinfection byproducts (DBPs). Some of these are mutagenic, genotoxic, teratogenic, and cytotoxic, as well as potentially carcinogenic both in vivo and in vitro. We investigated the in vitro biological activity of five DBPs: three monohaloacetic acids (monoHAAs) [chloroacetic acid (CAA), bromoacetic acid (BAA), and iodoacetic acid (IAA)] and two novel halobenzoquinones (HBQs) [2,6-dichloro-p-benzoquinone (DCBQ) and 2,6-dibromo-p-benzoquinone]. We focused particularly on cytotoxicity and induction of two adaptive stress response pathways: the oxidative stress responsive Nrf2/ARE and DNA-damage responsive p53 pathways. All five DBPs were cytotoxic to the Caco-2 cell line after a 4 h exposure, and all DBPs induced both of the adaptive stress response pathways, Nrf2/ARE and p53, in the micromolar range, as measured by two β-lactamase-based reporter gene assays. The decreasing order of potency for all three endpoints for the five DBPs was IAA ∼ BAA > DCBQ ∼ DBBQ > CAA. Induction of oxidative stress was previously proposed to be the molecular initiating event (MIE) for both classes of DBPs. However, comparing the levels of activation of the two pathways uncovered that the Nrf2/ARE pathway was the more sensitive endpoint for HAAs, whereas the p53 pathway was more sensitive in the case of HBQs. Therefore, the DNA damage-responsive p53 pathway may be an important piece of information to fill in a gap in the adverse outcome pathway framework for the assessment of HBQs. Finally, we cautiously compared the potential risk of the two novel HBQs using a benchmarking approach to that of the well-studied CAA, which suggested that their relative risk may be lower than that of BAA and IAA.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Procházka E,Escher BI,Plewa MJ,Leusch FDdoi
10.1021/acs.chemrestox.5b00283subject
Has Abstractpub_date
2015-10-19 00:00:00pages
2059-68issue
10eissn
0893-228Xissn
1520-5010journal_volume
28pub_type
杂志文章abstract::Electrochemical oxidation of drug molecules is a useful tool to generate several different types of metabolites. In the present study we developed a model system involving electrochemical oxidation followed by characterization of the oxidation products and their propensity to modify peptides. The CB1 antagonist rimona...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500255r
更新日期:2014-10-20 00:00:00
abstract::Zileuton, an inhibitor of 5-lipooxygenase, the initial enzyme in the leukotriene pathway, was marketed as a new treatment for asthma. This drug has been associated with liver toxicity, which has limited its clinical usefulness. We provide evidence here that the liver toxicity likely involves a sequence of biotransform...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0341409
更新日期:2004-02-01 00:00:00
abstract::Exposures to sulfur mustard (HD; bis(2-chloroethyll) sulfide) are well-known to result in the formation of adducts with free aspartate and glutamate residues of plasma proteins (Lawrence, R. J., Smith, J. R., and Capacio, B. R. 2008 32, (1), 31-36). A modified version of the analytical method reported previously for t...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00134
更新日期:2020-07-20 00:00:00
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::Recent reports by Galeazzi and co-workers demonstrated the susceptibility of Abeta(1-42) to undergo dityrosine formation via peroxidase-catalyzed tyrosine cross-linking. We have formed dityrosine cross-links in Abeta(1-40) using these enzymatic conditions as well as a copper-H(2)O(2) method. The efficiency of dityrosi...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx025666g
更新日期:2003-04-01 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 clinical use of the immunosuppressant calcineurin inhibitor cyclosporine is limited by its nephrotoxicity. This is enhanced when combined with the immunosuppressive mTOR inhibitor sirolimus. Nephrotoxicity of both drugs is not yet fully understood. The goal was to gain more detailed mechanistic insights into the t...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800253x
更新日期:2009-01-01 00:00:00
abstract::The present study describes a novel integrated approach for rapid analysis of reactive metabolites with a linear ion trap mass spectrometer (LTQ). In this approach, an isotope pattern-dependent scanning method was applied to the data acquisition of glutathione (GSH)-trapped reactive metabolites. Recorded full-scan MS ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx8001115
更新日期:2008-07-01 00:00:00
abstract::Both cooked red meat intake and chronic inflammation/infection are thought to play a role in the etiology of colon cancer. The heterocyclic amine 2-amino-3-methylimidazo[4,5-f ]quinoline (IQ) is formed during cooking of red meat and may be involved in initiation of colon cancer. Reactive nitrogen oxygen species (RNOS)...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx020008h
更新日期:2002-08-01 00:00:00
abstract::All pesticides must go through a rigorous risk assessment process in order to show that they are safe for use.With respect to dermal risk assessment for re-entry workers, the absorption value applied to predict systemic dose from this external exposure is obtained by testing liquid forms of the pesticide in vivo and/o...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500509z
更新日期:2015-02-16 00:00:00
abstract::There are discrepancies about whether chlorpyrifos is able to induce neurodevelopmental toxicity or not. We previously reported alterations in the pattern of expression of biomarker genes of differentiation in D3 mouse embryonic stem cells caused by chlorpyrifos and its metabolites chlorpyrifos-oxon and 3,5,6-trichlor...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500051k
更新日期:2014-09-15 00:00:00
abstract::Diethylstilbestrol (DES) and hexestrol (HES) are carcinogenic synthetic estrogens. The major metabolites of these compounds are their catechol derivatives, 3'-OH-DES and 3'-OH-HES. Oxidation of these metabolites leads to the electrophilic quinones, which are presumably involved in the tumor-initiating process. A synth...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx970140v
更新日期:1998-05-01 00:00:00
abstract::Carbon-13 NMR spectroscopy was used to study the effects of the peroxisome proliferator perfluoro-n-decanoic acid (PFDA) on hepatic carbohydrate metabolism in male Fischer-344 rats. The data indicate that PFDA-treated rats display an inhibition in hepatic [1-13C]glucose and [3-13C]alanine utilization on day 5 posttrea...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00037a003
更新日期:1994-01-01 00:00:00
abstract::Mitomycin C (MC), a cytotoxic anticancer drug and bifunctional DNA DNA alkylating agent, induces cross-linking of the complementary strands of DNA. The DNA interstrand cross-links (ICLs) are thought to be the critical cytotoxic lesions produced by MC. Decarbamoyl mitomycin C (DMC) has been regarded as a monofunctional...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx020044g
更新日期:2002-11-01 00:00:00
abstract::Human exposure to abacavir, a primary alcohol antiretroviral, is associated with the development of immunological drug reactions in individuals carrying the HLA risk allele B*57:01. Interaction of abacavir with antigen presenting cells results in cell activation through an Hsp70-mediated Toll-like receptor pathway and...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400041v
更新日期:2013-07-15 00:00:00
abstract::The antioxidant properties of a number of water-soluble diorganyl tellurides have been investigated. These organotellurium compounds efficiently protect against peroxynitrite-mediated oxidation of dihydrorhodamine 123, hydroxylation of benzoate, and nitration of 4-hydroxyphenyl acetate. The peroxidation of the zinc st...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx990156g
更新日期:2000-01-01 00:00:00
abstract::Taconite mining involves potential exposure to non-asbestiform amphibole mineral fiber. More recent studies have demonstrated increased mortality from respiratory cancers and heart disease among workers in the taconite industry. This finding is not consistent with recent exposure assessment findings, nor is the toxico...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00472
更新日期:2016-02-15 00:00:00
abstract::Cells respond to stress by controlling gene expression at several levels, with little known about the role of translation. Here, we demonstrate a coordinated translational stress response system involving stress-specific reprogramming of tRNA wobble modifications that leads to selective translation of codon-biased mRN...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00004
更新日期:2015-05-18 00:00:00
abstract::Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess th...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300075j
更新日期:2012-10-15 00:00:00
abstract::Protein-xenobiotic adducts are byproducts of xenobiotic metabolism. While there is a correlation between protein adduction and target organ toxicity, a cause and effect relationship is not often clear. Naphthoquinone (NQ) and monocrotaline pyrrole (MCTP) are two pneumotoxic electrophiles that form covalent adducts wit...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx1002436
更新日期:2010-09-20 00:00:00
abstract::A new experimental model was designed to study the fate of globin adducts with styrene 7,8-oxide (SO), a metabolic intermediate of styrene and a model electrophilic compound. Rat erythrocytes were incubated with SO at 7 or 22 °C. Levels of specific amino acid adducts in globin were determined by LC/MS analysis of the ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00518
更新日期:2016-04-18 00:00:00
abstract::Polychlorinated biphenyls (PCBs) are one of the most refractory environmental pollutants. Because of their ubiquitous existence in the biological systems (including human body), it is important to investigate their toxic behavior. Our previous findings demonstrated that a high reactive metabolite of PCB, namely PCB29-...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00376
更新日期:2019-06-17 00:00:00
abstract::The pharmacodynamics of rat hepatic cytochrome P450 2B (P450 2B) induction by phenobarbital (PB) and two structural congeners, dl-5-ethyl-5-phenylhydantoin (EPH) and dl-5-ethyl-5-phenyloxazolidinedione (EPO), were investigated. The in vivo induction of P450 2B was probed in F344/NCr rats by measuring immunoreactive he...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00032a008
更新日期:1993-03-01 00:00:00
abstract::The present study investigated the oxidative metabolism of 2-naphthyl isothiocyanate catalyzed by rat liver microsomes. Incubation of 2-naphthyl isothiocyanate, microsomes, and NADPH yielded either N,N'-di-2-naphthylurea or, on inclusion of 2-aminofluorene in the incubations, N-2-naphthyl-N'-2-fluorenylurea. These ure...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00030a010
更新日期:1992-11-01 00:00:00
abstract::Tobacco smoking is one of the leading causes for oral cancer. Dibenzo[a,l]pyrene (DB[a,l]P), an environmental pollutant and a tobacco smoke constituent, is the most carcinogenic polycyclic aromatic hydrocarbon (PAH) tested to date in several animal models (target organs: skin, lung, ovary, and mammary tissues). We hav...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200188j
更新日期:2011-08-15 00:00:00
abstract::At high doses, green tea extracts and green tea's major active constituent, (-)-epigallocatechin gallate (EGCG), despite their generally perceived health benefits, have been suspected to cause hepatotoxicity in certain human populations. It has been reported that o-quinone metabolites of gallic acid or EGCG are causat...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00450
更新日期:2020-11-16 00:00:00
abstract::meso-2,3-Dimercaptosuccinic acid is an orally active chelating agent useful for the treatment of lead intoxication. Since it is believed to be extracellular in its distribution, analogs have been synthesized in a search for one that will enter the cell and successfully complete for firmly bound intracellular toxic hea...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00032a010
更新日期:1993-03-01 00:00:00
abstract::It is well-known that aromatic diamino-, dihydroxy-, and amino-hydroxy compounds, with NH(2) and OH groups in ortho- or para-positions relative to each other, are strong skin sensitizers. In this paper, we analyze published potency and cross-reactivity data, whereby animals sensitized to one of these compounds are cha...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx9000336
更新日期:2009-09-01 00:00:00
abstract::By using a combination of biochemical methods (i.e., endoglycosidase H digestion and immunoblot and plant lectin binding studies), it was verified that pig flavin-containing monooxygenase (FMO1) was N-glycosylated. By using mass spectrometry approaches [i.e., peptide mapping, gas chromatography/mass spectrometry, micr...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx980117p
更新日期:1998-10-01 00:00:00
abstract::The number of consumer products containing nanoparticles (NPs) experienced a rapid increase during the past decades. However, most studies of nanosafety have been conducted using only pure NPs produced in the laboratory, while the interactions with other ingredients in consumer products have rarely been considered so ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00428
更新日期:2020-05-18 00:00:00