Abstract:
:Stimulated monocytes and neutrophils generate hypochlorite (HOCl) via the release of the enzyme myeloperoxidase and hydrogen peroxide. HOCl is a key bactericidal agent, but can also damage host tissue. As there is a strong link between chronic inflammation and some cancers, we have investigated HOCl damage to DNA, RNA, and polynucleotides. Reaction of HOCl with these materials is shown to yield multiple semistable chloramines (RNHCl/RR'NCl), which are the major initial products, and account for 50-95% of the added HOCl. These chloramines decay by thermal and metal-ion catalyzed processes, to give nucleoside-derived, nitrogen-centered, radicals. The latter have been characterized by EPR spin trapping. The propensity for radical formation with polynucleotides is cytidine > adenosine = guanosine > uridine = thymidine. The rates of decay, and yield of radicals formed, are dependent on the nature of the nucleobase on which they are formed, with chloramines formed from ring heterocyclic amine groups being less stable than those formed on exocyclic amines (RNH2 groups). Evidence is presented for chlorine transfer from the former, kinetically favored, sites to the more thermodynamically favored exocyclic amines. EPR experiments have also provided evidence for the rapid addition of pyrimidine-derived nitrogen-centered radicals to other nucleobases to give dimers and the oxidation of DNA by radicals derived from preformed nucleoside chloramines. Direct reaction of HOCl with plasmid DNA gives rise to single- and double-strand breaks via chloramine-mediated reactions. Preformed nucleoside chloramines also induce plasmid cleavage, though this only occurs to a significant extent with unstable thymidine- and uridine-derived chloramines, where radical formation is rapid. Overall the data rationalize the preferential formation of chlorinated 2'-deoxycytidine and 2'-deoxyadenosine in DNA and suggest that DNA damage induced by HOCl, and preformed chloramines, occurs at sequence-specific sites.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Hawkins CL,Davies MJdoi
10.1021/tx015548dsubject
Has Abstractpub_date
2002-01-01 00:00:00pages
83-92issue
1eissn
0893-228Xissn
1520-5010pii
tx015548djournal_volume
15pub_type
杂志文章abstract::(R)-Thalidomide was oxidized to 5-hydroxythalidomide and 5'-hydroxythalidomide by NADPH-fortified liver microsomes from humans and monkeys. (R)-Thalidomide was hydroxylated more efficiently than (S)-thalidomide. Recombinant human P450s 3A4, 3A5, and 3A7 and monkey P450s 3A8 and 3A5 (coexpressed with NADPH-P450 reducta...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx900367p
更新日期:2010-06-21 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::Dimethylarsinic acid (DMAs(V)), the major urinary metabolite of inorganic arsenic, is weakly cytotoxic, whereas its reduced form, dimethylarsinous acid (DMAs(III)), is highly toxic. Although glutathione S-transferase omega 1 (GSTO1) and arsenic methyltransferase have been shown or thought to catalyze DMAs(V) reduction...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300505v
更新日期:2013-03-18 00:00:00
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 environmental contaminant benzo[c]phenanthrene (B[c]Ph) has weak carcinogenic activity in rodent bioassays; however, the fjord region diol epoxides of B[c]Ph, B[c]Ph-3,4-diol 1,2-epoxides (B[c]PhDE), are potent carcinogens. To determine the role of cytochrome P450 isozymes in the activation of B[c]Ph in MCF-7 cell...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960174n
更新日期:1997-05-01 00:00:00
abstract::Toxicological studies assessing the safety of compounds for humans frequently use in vitro systems to characterize toxic responses in combination with transcriptomic analyses. Thus far, changes have mostly been investigated at the mRNA level. Recently, microRNAs have attracted attention because they are powerful negat...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx2003799
更新日期:2012-04-16 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::Pyridoxamine (PM) is an effective inhibitor of the formation of the carcinogen acrylamide (AA) from its precursors in low-moisture model systems. Although AA is widely assumed to act by scavenging carbonyl compounds, no alternative pathways have to date been explored. In this work, we found AA to directly react with P...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx100293y
更新日期:2011-03-21 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::Double-strand breaks are widely accepted to be the most toxic form of DNA damage. Molecules that produce double-strand breaks via a single chemical event are typically very cytotoxic and far less common than those that form single-strand breaks. It was recently reported that a commonly formed C4'-radical produces doub...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00032
更新日期:2015-04-20 00:00:00
abstract::Thalidomide is an infamous teratogen and it is continuously being explored for its anticancer properties. Fibroblast growth factor receptors (FGFRs) are implicated in embryo development and cancer pathophysiology. With striking similarities observed between FGFR implicated conditions and thalidomide embryopathy, we hy...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00286
更新日期:2019-04-15 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::Acrolein is a highly toxic environmental pollutant that readily alkylates the epsilon-amino group of lysine residues in proteins. In model systems, such chemistry involves sequential addition of two acrolein molecules to a given nitrogen, forming bis-Michael-adducted species that undergo aldol condensation and dehydra...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0502387
更新日期:2005-11-01 00:00:00
abstract::Marine toxins such as brevetoxins and ciguatoxins are produced by dinoflagellates and can accumulate in seafood. These toxins affect humans through seafood consumption. Intoxication is mainly characterized by gastrointestinal and neurological disorders and, in most severe cases, by cardiovascular problems. To prevent ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0342262
更新日期:2004-04-01 00:00:00
abstract::The crystal structure of Rad4/Rad23, the yeast homolog of the human nucleotide excision repair (NER) lesion recognition factor XPC-RAD23B ( Min , J. H. and Pavletich , N. P. ( 2007 ) Nature 449 , 570 - 575 ) reveals that the lesion-partner base is flipped out of the helix and binds to amino acids of the protein. This ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400156a
更新日期:2013-07-15 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::Sudoxicam and meloxicam are nonsteroidal anti-inflammatory drugs (NSAIDs) from the enol-carboxamide class. While the only structural difference between the two NSAIDs is the presence of a methyl group on the C5-position of the 2-carboxamidothiazole motif in meloxicam, a marked difference in their toxicological profile...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800185b
更新日期:2008-09-01 00:00:00
abstract::Aminoglutethimide (AMG) is an aromatic amine aromatase inhibitor associated with a high incidence of idiosyncratic blood dyscrasias, especially agranulocytosis. Animal models of idiosyncratic drug reactions (IDRs) represent essential tools to study these reactions; however, there is currently no valid model of idiosyn...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400224j
更新日期:2013-08-19 00:00:00
abstract::Catechol estrogens (CE) are among the major metabolites of estrone (E1) and 17 beta-estradiol (E2). Oxidation of these metabolites to semiquinones and quinones could generate ultimate carcinogenic forms of E1 and E2. The 2,3- and 3,4-quinones of E1 and E2 were synthesized by MnO2 oxidation of the corresponding CE, fol...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00030a016
更新日期:1992-11-01 00:00:00
abstract::Hemoglobin adducts have been used to assess exposure to carcinogenic compounds in tobacco smoke. However, because of background levels in nonsmokers, most adducts that have been studied are not useful for monitoring low-level exposure. Bergmark [(1997) Chem. Res. Toxicol. 10, 78-84] showed that the level of adducts of...
journal_title:Chemical research in toxicology
pub_type: 临床试验,杂志文章
doi:10.1021/tx9900728
更新日期:1999-10-01 00:00:00
abstract::The issue of the safety of drug metabolites in humans is a complex one. In this commentary, a proposal is made regarding how to deal with drug metabolites observed in humans such that the safety of these molecules can be assured. The human radiolabeled ADME study, in which metabolites are identified and quantified in ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0602012
更新日期:2006-12-01 00:00:00
abstract::Iron (Fe) chelation therapy was initially designed to alleviate the toxic effects of excess Fe evident in Fe-overload diseases. However, the novel toxicological properties of some Fe chelator-metal complexes have shifted appreciable focus to their application in cancer chemotherapy. Redox-inactive Fe chelator complexe...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx700039c
更新日期:2007-05-01 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::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::Chloroethylnitrosoureas (CENUs) are bifunctional alkylating agents widely used for the clinical treatment of cancer. They exert anticancer activity by inducing DNA interstrand cross-links (ICLs) within GC base pairs to form dG-dC cross-links. This lesion inhibits DNA double strand separation during replication and tra...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500143b
更新日期:2014-07-21 00:00:00
abstract::Epidemiological evidence suggests a lower incidence of Parkinson's disease in smokers than in nonsmokers. This evidence, together with the lower levels of brain monoamine oxidase (MAO) activity in smokers and the potential neuroprotective properties of MAO inhibitors, prompted studies which led to the isolation and ch...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx000224v
更新日期:2001-05-01 00:00:00
abstract::Previously, we identified two distinct metabonomic phenotypes in Sprague-Dawley rats sourced from two different rooms (colonies) in the Charles River, Raleigh facility [Robosky, L. C., Wells, D. F., Egnash, L. A., Manning, M. L., Reily, M. D., and Robertson, D. G. (2005) Metabonomic identification of two distinct phen...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx700184u
更新日期:2007-10-01 00:00:00
abstract::Successful early attrition of potential problematic compounds is of great importance in the pharmaceutical industry. The lead compound in a recent project targeting neuropathic pain was susceptible to metabolic bioactivation, which produced reactive metabolites and showed covalent binding to protein. Therefore, as a p...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx5000409
更新日期:2014-06-16 00:00:00
abstract::N(6)-(2-Hydroxy-3-buten-1-yl)-2'-deoxyadenosine (N(6)-HB-dA I) and N(6),N(6)-(2,3-dihydroxybutan-1,4-diyl)-2'-deoxyadenosine (N(6),N(6)-DHB-dA) are exocyclic DNA adducts formed upon alkylation of the N(6) position of adenine in DNA by epoxide metabolites of 1,3-butadiene (BD), a common industrial and environmental che...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00166
更新日期:2015-07-20 00:00:00
abstract::Evidence from laboratory studies and clinical trials suggests that plant-derived polyphenolic compounds such as curcumin, resveratrol, or phloretin might be useful in the treatment of certain diseases (e.g., Alzheimer's disease) and acute tissue injury states (e.g., spinal cord trauma). However, despite this potential...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/acs.chemrestox.6b00300
更新日期:2016-12-19 00:00:00