Abstract:
:The tobacco-specific nitrosamines N'-nitrosonornicotine (NNN, 1) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 2) are potent carcinogens in rodents. Bioactivation of NNN and NNK by cytochrome P450 enzymes generates a pyridyloxobutylating agent 6, which alkylates DNA to produce pyridyloxobutyl (POB)-DNA adducts. POB-DNA adduct formation plays a critical role in NNN and NNK carcinogenicity in rodents. To further investigate the significance of this pathway, we developed a high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method for quantitative analysis of four POB-DNA adducts with known structures. The corresponding deuterated analogues were synthesized and used as internal standards. DNA samples, spiked with internal standards, were subjected to neutral thermal hydrolysis followed by enzymatic hydrolysis. The hydrolysates were partially purified by solid phase extraction prior to HPLC-ESI-MS/MS analysis. The method was accurate and precise. Excellent sensitivity was achieved, especially for O2-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine (O2-POB-dThd, 11) with a detection limit of 100 amol per mg DNA. DNA samples treated with different concentrations of 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc, 3) were subjected to HPLC-ESI-MS/MS analysis. 7-[4-(3-Pyridyl)-4-oxobut-1-yl]guanine (7-POB-Gua, 12) was the most abundant adduct, followed by O6-[4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (O6-POB-dGuo, 8), O2-POB-dThd, and O2-[4-(3-pyridyl)-4-oxobut-1-yl]cytosine (O2-POB-Cyt, 13). Lung and liver DNA isolated from NNK-treated rats were analyzed. Consistent with the in vitro data, 7-POB-Gua was the major POB-DNA adduct formed in vivo. However, levels of O6-POB-dGuo were the lowest of the four adducts analyzed, suggesting efficient repair of this adduct in vivo. In contrast to the other three adducts, O6-POB-dGuo was more abundant in lung than in liver. O2-POB-dThd appeared to be poorly repaired in vivo, and its levels were comparable to those of 7-POB-Gua. The results of this study provide a sensitive HPLC-ESI-MS/MS method for comprehensive quantitation of four POB-DNA adducts, support an important role of O6-POB-dGuo in NNK lung tumorigenicity in rats, and suggest that O2-POB-dThd may be a useful tobacco-specific DNA biomarker for future tobacco carcinogenesis studies.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Lao Y,Villalta PW,Sturla SJ,Wang M,Hecht SSdoi
10.1021/tx050351xsubject
Has Abstractpub_date
2006-05-01 00:00:00pages
674-82issue
5eissn
0893-228Xissn
1520-5010journal_volume
19pub_type
杂志文章abstract::The regulation of cellular stress responses to electrophiles and oxidants is mediated by the transcription factor NF-E2-related factor 2 (Nrf2), which, in turn, is regulated by CUL-E3 (CUL3) ligase-mediated ubiquitylation. The Kelch-like ECH-associated protein 1 (Keap1) serves as an adapter between CUL3 and Nrf2. We u...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx700302s
更新日期:2008-03-01 00:00:00
abstract::The growth-promoting effects of estrogens in hormone-dependent tumor tissues involve receptor-mediated pathways that are well-recognized; however, the role of estrogens in tumor initiation remains controversial. Estrogen metabolites, primarily the catechol estrogens (CE's), have been implicated in tumor initiation via...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx980128i
更新日期:1999-03-01 00:00:00
abstract::Epidemiologic studies have shown causal relationships between air pollution particles and adverse health effects in susceptible subpopulations. Fly ash particles (containing water-soluble and insoluble metals) are a component of ambient air particulate pollution and may contribute to particulate-induced health effects...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx000110j
更新日期:2000-10-01 00:00:00
abstract::During our ongoing studies of the reactions of toluene diisocyanate (2,4- and 2,6-diisocyanatotoluene, TDI) in vivo, it became apparent that reactive form(s) of these diisocyanates reach(es) the circulatory system after passage through the respiratory system. Based on recent work by others regarding the transcarbamoyl...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960201+
更新日期:1997-04-01 00:00:00
abstract::Toxicity data for 82 aliphatic chemicals with an alpha,beta-unsaturated substructure were compiled. Toxicity was assessed in the 2-day Tetrahymena pyriformis population growth impairment assay. Toxic potency [log(IGC50(-1))] for most of these chemicals was in excess of baseline narcosis as quantified by the 1-octanol/...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx049833j
更新日期:2005-02-01 00:00:00
abstract::To reveal the roles of Y family DNA polymerases in the mutagenesis induced by oxidatively damaged DNA precursors, 2-hydroxy-dATP (2-OH-dATP) and 8-hydroxy-dGTP (8-OH-dGTP) were introduced into Escherichia coli strains deficient in the Y family polymerases, DNA polymerase IV (pol IV, encoded by the dinB gene) and DNA p...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050046b
更新日期:2005-08-01 00:00:00
abstract::One possible mechanism linking inflammation with cancer involves the generation of reactive oxygen, nitrogen, and halogen species by activated macrophages and neutrophils infiltrating sites of infection or tissue damage, with these chemical mediators causing damage that ultimately leads to cell death and mutation. To ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300473n
更新日期:2013-04-15 00:00:00
abstract::The synthesis of a series of 1,2,4-triazole-containing oligopeptide lexitropsins related to the natural antitumor antibiotic distamycin is described. The binding properties of these new agents to both native DNAs and synthetic polydeoxyribonucleotides were determined by UV absorption and circular dichroism studies. Th...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00020a019
更新日期:1991-03-01 00:00:00
abstract::Topoisomerase II regulates DNA topology by generating transient double-stranded breaks. The anticancer drug etoposide targets topoisomerase II and is associated with the formation of secondary leukemias in patients. The quinone and catechol metabolites of etoposide may contribute to strand breaks that trigger leukemic...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400205n
更新日期:2013-08-19 00:00:00
abstract::Many herbal medicines such as epimedium have been reported to cause adverse effects, and icaritin is the common aglycone of many glucosides in epimedium. Our present work aimed at the clarification of the metabolic activation of icaritin possibly responsible for the adverse effects of epimedium. A quinone methide meta...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00418
更新日期:2019-06-17 00:00:00
abstract::( E)-4-Hydroxynon-2-enal (HNE), an electrophilic bifunctional cytotoxic lipid peroxidation product, forms covalent adducts with nucleophilic side chains of amino acid residues. HNE-derived adducts have been implicated in many pathophysiological processes including atherosclerosis, diabetes, and Alzheimer's disease. Tr...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx8000303
更新日期:2008-07-01 00:00:00
abstract::Tetrabromobisphenol A, a brominated flame retardant, is increasingly prevalent worldwide and presents a potential health risk. Adjusted animal biomonitoring equivalents of tetrabromobisphenol A after orally administered doses in humanized-liver mice were scaled up to humans using known species allometric scaling facto...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00358
更新日期:2020-11-16 00:00:00
abstract::Sex-, species-, and chain length-dependent renal elimination is the hallmark of mammalian elimination of perfluorocarboxylates (PFCAs) and has been extensively studied for almost 30 years. In this review, toxicokinetic data of PFCAs (chain lengths ranging from 4 to 10) in different species are compared with an emphasi...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx200363w
更新日期:2012-01-13 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::Flucloxacillin, an isoxazolyl-penicillin, causes cholestasis and biliary epithelium injury. The aim of the study was to determine whether flucloxacillin, either directly or through metabolite formation, may induce cytotoxicity in hepatic or biliary cells. Cytotoxicity was assessed by lactate dehydrogenase release in p...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0002435
更新日期:2001-06-01 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::3-(2-Deoxy-beta-D-erythro-pentofuranosyl)-6-hydroxy-5,6,7,8-tetrahydropyrimido[1,2-a]purin-10(3H)-one is formed in low yield by the reaction of acrolein with 2'-deoxyguanosine. The nucleoside and an oligodeoxynucleotide containing it have been synthesized. For preparation of the nucleoside 2'-deoxyguanosine was alkyla...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx010181y
更新日期:2002-05-01 00:00:00
abstract::Although the causes of Parkinson's disease (PD) are not fully understood, the consensus is that a combination of genetic and environmental factors plays a major role. The discovery that the synthetic chemical, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-derived N-methyl-4-phenylpyridinium (MPP+), recapitulates...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00422
更新日期:2021-01-26 00:00:00
abstract::alpha-Sulfate trans-tamoxifen and alpha-sulfate cis-tamoxifen were synthesized as proposed active metabolites of tamoxifen that react with DNA. alpha-Acetoxytamoxifen was prepared as a model-activated form to produce a reactive carbocation. Calf thymus DNA was reacted with alpha-hydroxytamoxifen or the activated forms...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960114h
更新日期:1997-02-01 00:00:00
abstract::Adverse events resulting from drug therapy can be a cause of drug withdrawal, reduced and or restricted clinical use, as well as a major economic burden for society. To increase the safety of new drugs, there is a need to better understand the mechanisms causing the adverse events. One way to derive new mechanistic hy...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00159
更新日期:2018-11-19 00:00:00
abstract::It has previously been shown that malonaldehyde forms conjugates with acetaldehyde and that these conjugates react with nucleobases forming so-called conjugate adducts. In the current study, it is shown that conjugate adducts are also formed in calf thymus DNA when incubated simultaneously with malonaldehyde and aceta...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx060027h
更新日期:2006-07-01 00:00:00
abstract::Experimental and epidemiological data associate the exposure of estrogens to cancer development in several tissues, particularly, the breast, endometrium, liver, and kidney. One plausible mechanism of estrogen-mediated carcinogenicity is DNA damage by redox cycling of estrogen catechols. Reports have shown that metabo...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200356v
更新日期:2012-02-20 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::Contact allergy is caused by a wide range of chemicals after skin contact. Its clinical manifestation, allergic contact dermatitis (ACD), is developed upon repeated contact with the allergen. This perspective focuses on two areas that have yielded new useful information during the last 20 years: (i) structure-activity...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx7002239
更新日期:2008-01-01 00:00:00
abstract::The chemical reactivities of the optically-pure fjord-region syn- and anti-benzo[g]chrysene 11,12-dihydrodiol 13,14-epoxides (B[g]CDEs) toward DNA in vitro have been compared with those of the optically-pure fjord-region syn- and anti-benzo[c]phenanthrene 3,4-dihydrodiol 1,2-epoxides (B[c]PhDEs), using the standard 32...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00046a014
更新日期:1995-06-01 00:00:00
abstract::The mechanisms underlying aryl hydrocarbon receptor (AHR) activation by agonists and circumstances that increase the sensitivity toward agonists and AHR inhibition by antagonists are diverse and still not fully understood. AHR antagonist, 2-methyl-2 H-pyrazole-3-carboxylic acid (2-methyl-4- o-tolylazo-phenyl)-amide, C...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00371
更新日期:2019-04-15 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::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::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::S-(1,2-Dichlorovinyl)-L-cysteine (DCVC), a mutagenic and nephrotoxic metabolite of trichloroethylene, is bioactivated to S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS) and chlorothioketene and/or 2-chlorothionoacetyl chloride by cysteine conjugate S-oxidase (S-oxidase) and cysteine conjugate beta-lyase (beta-lyase...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx900219x
更新日期:2009-09-01 00:00:00