Abstract:
:N-Nitrosopyrrolidine (NPYR) is a well-established hepatocarcinogen in the rat. NPYR requires metabolic activation by cytochrome P450-catalyzed alpha-hydroxylation to express its carcinogenic activity. This produces alpha-hydroxyNPYR (2), which spontaneously ring opens to 4-oxobutanediazohydroxide (4), a highly reactive intermediate, which may itself modify DNA or yield a cascade of electrophiles that react with DNA to produce adducts. Multiple dGuo adducts formed in this reaction have been previously characterized, but there are no examples of adducts formed with other DNA nucleobases. In this study, we used alpha-acetoxyNPYR (3) as a stable precursor to 2 and 4. Compound 3 was allowed to react with DNA. The DNA was enzymatically hydrolyzed to deoxyribonucleosides, and the products were analyzed by LC-ESI-MS and LC-ESI-MS/MS. Reactions of 3 with individual deoxyribonucleosides were also carried out. The products were identified by their MS, UV, and NMR spectra as N6-(tetrahydrofuran-2-yl)dAdo (16) and N4-(tetrahydrofuran-2-yl)dCyd (17) in addition to the previously characterized N2-(tetrahydrofuran-2-yl)dGuo (13). Unstable dThd adducts were also formed. Further characterization of the adducts was achieved by NaBH3CN reduction of the reaction mixtures of 3 with deoxyribonucleosides or DNA. This produced N6-(4-hydroxybut-1-yl)dAdo (21), N4-(4-hydroxybut-1-yl)dCyd (22), O2-(4-hydroxybut-1-yl)dThd (23), O4-(4-hydroxybut-1-yl)dThd (24), and 3-(4-hydroxybut-1-yl)dThd (25). Adducts 21 and 22 were characterized by their spectral properties, while the dThd adducts 23-25 were identified by comparison to synthetic standards. The results of this study demonstrate that 3 forms adducts with dAdo, dCyd, and dThd in DNA, in addition to the previously characterized dGuo adducts. These newly characterized standards can be used to investigate DNA adduct formation in rats treated with NPYR.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Wang M,Lao Y,Cheng G,Shi Y,Villalta PW,Hecht SSdoi
10.1021/tx600332psubject
Has Abstractpub_date
2007-04-01 00:00:00pages
625-33issue
4eissn
0893-228Xissn
1520-5010journal_volume
20pub_type
杂志文章abstract::A series of tether-linked bis netropsins have been synthesized in order to assess the phasing problem, which arises because of the lack of dimensional correspondence between oligopeptides and oligonucleotides in DNA binding characteristics. The consequences of incorporating variable-length flexible and rigid tethers [...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00014a013
更新日期:1990-03-01 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::Hypoxia-inducible factor-1α (HIF-1α) is a critical regulator of cellular responses to hypoxia. Under normoxic conditions, the cellular HIF-1α level is regulated by hydroxylation by prolyl hydroxylases (PHDs), ubiquitylation, and proteasomal degradation. During hypoxia, degradation decreases, and its intracellular leve...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300274a
更新日期:2012-10-15 00:00:00
abstract::The tumorigenic activity of manufactured gas plant residue (MGP) was evaluated in female A/J mice using a F0927 basal gel diet system. Adulterated diets containing MGP (0.10% or 0.25%) or benzo[a]pyrene (B[alpha]P; 16 or 98 ppm) were fed for 260 days. A negative control group was maintained on a nonadulterated basal g...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00049a008
更新日期:1995-10-01 00:00:00
abstract::The mechanism of the hepatotoxicity of the analgesic acetaminophen is believed to be mediated by covalent binding to protein; however, critical targets which effect the toxicity are unknown. It has been shown that mitochondrial respiration in vivo is inhibited in mice as early as 1 h following a hepatotoxic dose of ac...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx950158a
更新日期:1996-03-01 00:00:00
abstract::In recent years, there has been an increase in the production of shellfish and in global demand for seafood as nutritious and healthy food. Unfortunately, a significant number of incidences of shellfish poisoning occur worldwide, and microalgae that produce phycotoxins are responsible for most of these. Phycotoxins in...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx200182m
更新日期:2011-11-21 00:00:00
abstract::For decades, many studies have linked maternal smoking to an increased risk of preterm birth. As a result, the scientific community has long hypothesized that exposure to environmental tobacco smoke (ETS), commonly referred to as second-hand smoke, is also associated with an increased risk of preterm birth. Multiple s...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.7b00054
更新日期:2017-07-17 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::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::Oxidized nucleobases represent one of the main classes of damage induced in DNA by ionizing radiation. Emphasis was placed in this work on the measurement of four oxidized pyrimidine bases, including 5-(hydroxymethyl)uracil (5-HMUra), 5-formyluracil (5-ForUra), 5-hydroxycytosine (5-OHCyt), and 5-hydroxyuracil (5-OHUra...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960095b
更新日期:1996-10-01 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::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::The gender differences in the in vitro microsomal metabolic activation of hepatotoxic clivorine, a representative naturally occurring hepatotoxic otonecine type pyrrolizidine alkaloid, in Sprague-Dawley rats and their relation to the gender differences in susceptibility to clivorine intoxication were reported in the p...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0340302
更新日期:2003-06-01 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::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::The oral dipeptidyl peptidase 1 (DPP1) inhibitor AZD5248 showed aortic binding in a rat quantitative whole-body autoradiography (QWBA) study, and its development was terminated prior to human dosing. A mechanistic hypothesis for this finding was established invoking reactivity with aldehydes involved in the cross-link...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00236
更新日期:2015-10-19 00:00:00
abstract::Acrolein is a bifunctional electrophile, present as an ubiquitous environmental pollutant and an endogenous cellular product of lipid peroxidation. Reaction of acrolein with deoxyguanosine produces two regioisomeric DNA adducts, specifically gamma-hydroxypropanodeoxyguanosine (gamma-HOPdG) and alpha-hydroxypropanodeox...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx034066u
更新日期:2003-08-01 00:00:00
abstract::This work reveals a novel mechanism for triplet carbonyl formation (and hence chemiluminescence) during lipid peroxidation, whose chemiluminescence has been attributed to both triplet carbonyls and singlet oxygen. As a model for polyunsaturated fatty acid hydroperoxides, we have synthesized 3-hydroperoxy-2,3-dimethyl-...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx970075p
更新日期:1997-10-01 00:00:00
abstract::2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic aromatic amine that is formed during the cooking of meats. PhIP is a potential human carcinogen: it undergoes metabolic activation to form electrophilic metabolites that bind to DNA and proteins, including serum albumin (SA). The structures of Ph...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300253j
更新日期:2012-10-15 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::The chemical reactivity of styrene-7,8-oxide (SO), an alkylating agent with high affinity for the guanine–N7 position and a probable carcinogen for humans, with 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases, was investigated kinetically in...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx5002892
更新日期:2014-10-20 00:00:00
abstract::Notopterygium forbesii Boiss (NF) has been used as a traditional Chinese medicine for the treatment of common cold and rheumatism. However, there has been limited research on the biological properties of NF, and the mechanisms of action remain unknown. Here, we aimed to study the mechanism of NF-induced heme oxygenase...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800301f
更新日期:2008-12-01 00:00:00
abstract::The formation of 8-oxo-7,8-dihydroguanine (G(O), 8-hydroxyguanine) in DNA and in the nucleotide pool results in G:C→T:A and A:T→C:G substitution mutations, respectively, since G(O) can pair with both C and A. In this study, the role of DNA polymerase κ in the mutagenicity of G(O) was investigated, using a supF shuttle...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300259x
更新日期:2012-08-20 00:00:00
abstract::A new procedure has been developed for the extraction of 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) and other heterocyclic aromatic amines from human breast milk samples. Extracts were analyzed by high-performance liquid chromatography/electrospray ionization/tandem mass spectrometry (HPLC/ESI-MS/MS) with...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0601861
更新日期:2007-01-01 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::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::Bleomycin has a long-studied mechanism of action through the formation of a complex with metals, such as iron. The bleomycin-iron complex was recently shown to induce membrane damage by free radical reactivity. Because the use of Fe nanoparticles is spreading for drug delivery strategies, molecular mechanisms of cell ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00162
更新日期:2020-10-19 00:00:00
abstract::The hepatic metabolism of microcystins (MCs), potent cyclic peptide hepatotoxins produced by cyanobacteria, was studied by i.p. injection in mice and rats. An immunoaffinity purification method using an anti-MC-LR monoclonal antibody showed a remarkable effect on the removal of contaminants in the hepatic cytosol and ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960085a
更新日期:1996-12-01 00:00:00
abstract::Metabolically formed dihydrodiol epoxides in the bay-region of polycyclic aromatic hydrocarbons are thought to be responsible for the genotoxic properties of these environmental pollutants. The hexacyclic aromatic hydrocarbon dibenzo[def,mno]chrysene (anthanthrene), although lacking this structural feature, was found ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx010131t
更新日期:2002-03-01 00:00:00
abstract::Metabolic pathways of the mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) remain incompletely characterized in humans. In this study, the metabolism of MeIQx was investigated in primary human hepatocytes. Six metabolites were characterized by UV and mass spectroscopy. Novel metabolites were additionally ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx000176e
更新日期:2001-02-01 00:00:00