Abstract:
:The Escherichia coli NarI restriction enzyme recognition site 5'G1G2C3G4C5C63' is a mutational hotspot for -2 deletions in E. coli plasmid pBR322, resulting in the sequence 5'GGCC3' when G4 is modified by the aromatic amine N-2-(acetyl)aminofluorene (AAF) [Burnouf, D., Koehl, P., and Fuchs, R. P. P. (1995) Proc. Natl. Acad. Sci. U.S.A. 86, 4147-4151] even though each G shows similar reactivity [Fuchs, R. P. P. (1984) J. Mol. Biol. 177, 173-180]. Modification at G4 by the related aromatic amine 2-aminofluorene (AF), which lacks the acetyl group of AAF, can also cause -2 deletions, but at a lower frequency [Bichara, M., and Fuchs, R. P. P. (1985) J. Mol. Biol. 183, 341-351]. A specific mechanism has been proposed to explain the double-base frameshifts in the NarI sequence in which the GC deletion results from a slipped mutagenic intermediate formed during replication [Schaaper, B. M., Koffel-Schwartz, N., and Fuchs, R. P. P. (1990) Carcinogenesis 11, 1087-1095]. We address the following key questions in this study. Why does AAF modification dramatically increase the mutagenicity at the NarI G4 position, and why does AAF enhance the mutagenicity more than AF? We studied two intermediates which model replication at one arm of a fork, using a fragment of DNA modified by AF or AAF at G4 in the NarI sequence: Intermediate I can be converted into intermediate II by misalignment. Elongation of intermediate I leads to error-free translesion synthesis, while elongation of intermediate II leads to a -2 frameshift mutation. Minimized potential energy calculations were carried out using the molecular mechanics program DUPLEX to investigate the conformations of the AF and AAF adducts at G4 in these two intermediates. We find that the slipped mutagenic intermediate is quite stable relative to its normally extended counterpart in the presence of AF and AAF in an abnormal syn orientation of the damaged base. An enhanced probability of elongation from a stable slipped structure rather than a properly aligned one would favor increased -2 frameshift mutations. Furthermore, AAF-modified DNA has a greater tendency to adopt the syn orientation than AF because of its greater bulk, which could explain its greater propensity to cause -2 deletions in the NarI sequence.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Roy D,Hingerty BE,Shapiro R,Broyde Sdoi
10.1021/tx980106wsubject
Has Abstractpub_date
1998-11-01 00:00:00pages
1301-11issue
11eissn
0893-228Xissn
1520-5010pii
tx980106wjournal_volume
11pub_type
杂志文章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::Deoxynivalenol (DON) is a trichothecene mycotoxin that is produced by several species of Fusarium, which may infect grain crops. DON, as well as other type-B trichothecenes, contain an α,β-unsaturated carbonyl group that may react with sulfhydryl groups in, for example, amino acids and peptides. Such conjugates have b...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00385
更新日期:2020-02-17 00:00:00
abstract::The reaction of chromium(VI) with hydrogen peroxide was studied in the presence of glutathione. In vitro, reaction of chromium(VI) with hydrogen peroxide alone led to production of hydroxyl radical as the significant reactive intermediate, while reaction of chromium(VI) with glutathione led to formation of two chromiu...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00018a016
更新日期:1990-11-01 00:00:00
abstract::Deferoxamine is an inhibitor of iron-dependent free radical reactions. Despite the antioxidant roles, prolonged clinical use of the chelator is far from benign, and paradoxically, deferoxamine has been shown to promote lipid peroxidation. The possible toxicity of the drug's metabolites, such as deferoxamine nitroxide ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx980212y
更新日期:1999-02-01 00:00:00
abstract::The hydroperoxide of linoleic acid (13-HPODE) degrades to 9,12-dioxo-10(E)-dodecenoic acid (DODE), which readily modifies proteins. This study identified the major proteins in MCF7 cells modified by DODE. To reduce false positives, three methods were used to identify DODE-modified proteins. First, cells were treated w...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx9002808
更新日期:2010-03-15 00:00:00
abstract::Reactive oxygen species can induce the formation of tandem DNA lesions. We recently showed that the treatment of calf thymus DNA with Cu2+/H2O2/ascorbate could result in the efficient formation of a tandem lesion where a 5,6-dihydroxy-5,6-dihydrothymidine (or thymidine glycol) is situated on the 5' side of an 8-oxo-7,...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx8003449
更新日期:2009-03-16 00:00:00
abstract::Studies on the metabolic bioactivation of the psychotomimetic amine phencyclidine have been pursued through the characterization of a new metabolite which is formed via initial cytochrome P-450 catalyzed oxidation of the parent drug to the corresponding iminium species. CI mass spectrometric and diode array UV and 1H ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00002a007
更新日期:1988-03-01 00:00:00
abstract::Smokeless tobacco products, such as moist snuff or chewing tobacco, contain many of the same carcinogens as tobacco smoke; however, the impact on children of indirect exposure to tobacco constituents via parental smokeless tobacco use is unknown. As part of the California Childhood Leukemia Study, dust samples were co...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00040
更新日期:2015-05-18 00:00:00
abstract::Methyleugenol (ME), an alkenylbenzene compound, is a natural ingredient of several herbs and is used as flavoring agent in foodstuffs and fragrance in cosmetics. The hepatotoxicity, cytotoxicity, and carcinogenesis of ME have been well documented, and metabolic activation has been suggested to involve in ME-induced to...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.6b00290
更新日期:2017-02-20 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::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::Spin-trapping with 5,5-dimethyl-1-pyrroline 1-oxide (DMPO) was used to demonstrate that 3-nitrotyrosine (nitrotyrosine) promotes the formation of substantial amounts of reactive oxygen species (O2.- and *OH), when incubated with NAD(H)-cytochrome c reductase and a corresponding electron donor. Spin adduct formation is...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx970201p
更新日期:1998-05-01 00:00:00
abstract::We have reassigned relative and absolute configurations by unambiguous stereoselective syntheses of the cis- (13s and 13R) and trans-N6-deoxyadenosine (dAdo) adduct diastereomers (14S and 14R) derived from (+/-)-11beta,12alpha-dihydroxy-13alpha,14alpha-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]P DE-2), pr...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800268f
更新日期:2008-12-01 00:00:00
abstract::There is interest in the relative toxicities of emissions from electronic cigarettes and tobacco cigarettes. Lists of cigarette smoke priority toxicants have been developed to focus regulatory initiatives. However, a comprehensive assessment of e-cigarette chemical emissions including all tobacco smoke Harmful and Pot...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.6b00188
更新日期:2016-10-17 00:00:00
abstract::The crystal structure of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) has been determined by single-crystal X-ray crystallography. Crystals grown by evaporation of an aqueous solution form in the monoclinic space group P2(1)/n with two molecules of PhIP per asymmetric unit, along with six w...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx950168b
更新日期:1996-04-01 00:00:00
abstract::Enzymatic methylation of cytosine residues in DNA, in conjunction with covalent histone modifications, establishes an epigenetic code essential for the proper control of gene expression in higher organisms. Once established during cellular differentiation, the epigenetic code must be faithfully transmitted to progeny ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx900027w
更新日期:2009-06-01 00:00:00
abstract::Ochratoxin A (OTA) is a mycotoxin that shows potent nephrotoxicity and renal carcinogenicity in rodents. One hypothesis for OTA-induced tumor formation is based on its genotoxic properties that are promoted by oxidative metabolism. Like other chlorinated phenols, OTA undergoes an oxidative dechlorination process to ge...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx060138g
更新日期:2006-09-01 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::Pyrrolizidine alkaloids (PAs) are known hepatotoxins. The execution of the toxicities of the alkaloids requires metabolic activation. Protein modification by reactive metabolites of PAs has been suggested to be an important mechanism of the toxic actions of PAs. The objectives of the present study were to define the i...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00488
更新日期:2016-03-21 00:00:00
abstract::Oxidation of low-density lipoproteins (LDL) is believed to contribute to the increased uptake of LDL by macrophages, which is an early event in atherosclerosis. Hypochlorous acid (HOCl) has been implicated as one of the major oxidants involved in these processes. In a previous study, the rates of reaction of HOCl with...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx025670s
更新日期:2003-04-01 00:00:00
abstract::Skin sensitizers chemically modify skin proteins rendering them immunogenic. Sensitizing chemicals have been divided into applicability domains according to their suspected reaction mechanism. The widely accepted Schiff base applicability domain covers aldehydes and ketones, and detailed structure-activity-modeling fo...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300278t
更新日期:2012-10-15 00:00:00
abstract::Two samples of highly pure multiwalled carbon nanotubes (MWCNTs) similar in hydrophobicity and surface reactivity were prepared with similar length, <5 μm, but markedly different diameter (9.4 vs 70 nm). The samples were compared for their cytotoxic activity, uptake, and ability to induce oxidative stress (ROS product...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200255h
更新日期:2012-01-13 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::The measurement of metabolites constitutes a useful tool for detection of exposure and in pharmacokinetic studies. Epoxidation with subsequent glutathione conjugation and mercapturic acid formation is an important deactivation pathway for naphthalene, a toxin which presumably causes lung disease. The mercapturic acid ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00033a006
更新日期:1993-05-01 00:00:00
abstract::Organic electrophiles have been recognized as important components of the exposome that can be characterized as cumulative totality of exposure in the organism in response to environmental perturbation. For such compounds, chemical reactivity may contribute significantly to the toxicological profile through covalent a...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00398
更新日期:2016-06-20 00:00:00
abstract::The activity of three metabolically activated methylating agents, N-methyl-N-(acetoxymethyl)nitrosamine (DMN-OAc), methylnitrosourethane (MNUT), and (methylazoxy)methanol acetate (MAM-Ac), were determined in cell culture by using a P388 cell growth rate inhibition assay. Experiments were conducted with normal P388 cel...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00011a004
更新日期:1989-09-01 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::Nickel(II) compounds are established human carcinogens, but the molecular mechanisms underlying their activity are only partially known. One mechanism may include mediation by nickel of promutagenic oxidative DNA damage that depends on Ni(II) binding to chromatin. To characterize such binding at the histone moiety of ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00047a007
更新日期:1995-07-01 00:00:00
abstract::Dibenzo[a,l]pyrene (DB[a,l]P) is one of the most potent carcinogens ever tested in mouse skin and rat mammary gland. DB[a,l]P is present in cigarette smoke and, presumably, in other environmental pollutants. Metabolism and mutagenicity studies of this compound compared to the weak carcinogen dibenzo[a,e]pyrene (DB[a,e...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00018a014
更新日期:1990-11-01 00:00:00
abstract::This study was designed to distinguish and evaluate the contribution of reactive metabolite and reactive oxygen species as the mechanism of metabolism-dependent valproic acid-induced in vitro cytotoxicity. The involvement of reactive oxygen species in the mechanism of in vitro cytotoxicity was examined by the addition...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx9801864
更新日期:1999-04-01 00:00:00