Two-Mechanism Model for the Interaction of Etoposide Quinone with Topoisomerase IIα.

Abstract:

:Topoisomerase II is an essential nuclear enzyme involved in regulating DNA topology to facilitate replication and cell division. Disruption of topoisomerase II function by chemotherapeutic agents is in use as an effective strategy to fight cancer. Etoposide is an anticancer therapeutic that disrupts the catalytic cycle of topoisomerase II and stabilizes enzyme-bound DNA strand breaks. Etoposide is metabolized into several species including active quinone and catechol metabolites. Our previous studies have explored some of the details of how these compounds act against topoisomerase II. In our present study, we extend those analyses by examining several effects of etoposide quinone on topoisomerase IIα including whether the quinone impacts ATP hydrolysis, DNA ligation, cleavage complex persistence, and enzyme/DNA binding. Our results demonstrate that the quinone inhibits relaxation at 100-fold lower levels of drug when compared to that of etoposide. Further, the quinone inhibits ATP hydrolysis by topoisomerase IIα. The quinone does appear to stabilize single-strand breaks similar to etoposide suggesting a traditional poisoning mechanism. However, there is minimal difference in cleavage complex persistence in the presence of etoposide or etoposide quinone. In contrast to etoposide, we find that etoposide quinone blocks enzyme/DNA binding, which provides an explanation for previous data showing the ability of the quinone to inactivate the enzyme over time. Finally, etoposide quinone is able to stabilize the N-terminal protein clamp implying an interaction between the compound and this portion of the enzyme. Taken together, the evidence supports a two-mechanism model for the effect of the quinone on topoisomerase II: (1) interfacial poison and (2) covalent poison that interacts with the N-terminal clamp and impacts the binding of DNA.

journal_name

Chem Res Toxicol

authors

Gibson EG,King MM,Mercer SL,Deweese JE

doi

10.1021/acs.chemrestox.6b00209

subject

Has Abstract

pub_date

2016-09-19 00:00:00

pages

1541-8

issue

9

eissn

0893-228X

issn

1520-5010

journal_volume

29

pub_type

杂志文章
  • Potential Modulation of Human NAD[P]H-Quinone Oxidoreductase 1 (NQO1) by EGCG and Its Metabolites-A Systematic Computational Study.

    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

    authors: Pandey P,Avula B,Khan IA,Khan SI,Navarro VJ,Doerksen RJ,Chittiboyina AG

    更新日期:2020-11-16 00:00:00

  • Rapid screening of glutathione-trapped reactive metabolites by linear ion trap mass spectrometry with isotope pattern-dependent scanning and postacquisition data mining.

    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

    authors: Ma L,Wen B,Ruan Q,Zhu M

    更新日期:2008-07-01 00:00:00

  • Sustained systemic delivery of green tea polyphenols by polymeric implants significantly diminishes benzo[a]pyrene-induced DNA adducts.

    abstract::The polyphenolics in green tea are believed to be the bioactive components. However, poor bioavailability following ingestion limits their efficacy in vivo. In this study, polyphenon E (poly E), a standardized green tea extract, was administered by sustained-release polycaprolactone implants (two, 2-cm implants; 20% d...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx2000625

    authors: Cao P,Vadhanam MV,Spencer WA,Cai J,Gupta RC

    更新日期:2011-06-20 00:00:00

  • Identification and quantification of DNA adducts in the oral tissues of mice treated with the environmental carcinogen dibenzo[a,l]pyrene by HPLC-MS/MS.

    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

    authors: Zhang SM,Chen KM,Aliaga C,Sun YW,Lin JM,Sharma AK,Amin S,El-Bayoumy K

    更新日期:2011-08-15 00:00:00

  • Experimental Exposure Assessment of Ionizable Organic Chemicals in In Vitro Cell-Based Bioassays.

    abstract::Exposure assessment in in vitro cell-based bioassays is challenging for ionizable organic chemicals (IOCs), because they are present as more than one chemical species in the bioassay medium. Furthermore, compared to neutral organic chemicals, their binding to medium proteins and lipids is driven by more complex molecu...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/acs.chemrestox.0c00067

    authors: Huchthausen J,Mühlenbrink M,König M,Escher BI,Henneberger L

    更新日期:2020-07-20 00:00:00

  • DNA adducts of acrolein: site-specific synthesis of an oligodeoxynucleotide containing 6-hydroxy-5,6,7,8-tetrahydropyrimido[1,2-a]purin-10(3H)-one, an acrolein adduct of guanine.

    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

    authors: Nechev LV,Kozekov ID,Brock AK,Rizzo CJ,Harris TM

    更新日期:2002-05-01 00:00:00

  • Synthesis of the PhIP adduct of 2'-deoxyguanosine and its incorporation into oligomeric DNA.

    abstract::The 2'-deoxyguanosine adduct of the dietary mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) has been synthesized and incorporated into DNA using solid state synthesis technology. The key step to obtaining the C8-dG adduct is a palladium (Xantphos-chelated)-catalyzed N-arylation (Buchwald-Hartwig reactio...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx0600191

    authors: Bonala R,Torres MC,Iden CR,Johnson F

    更新日期:2006-06-01 00:00:00

  • Activation of phospholipase A2 in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes containing lipid ozonation products.

    abstract::The activation of phospholipase A2 (PLA2) by lipid ozonation products is reported. The principal products from the ozonation of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) are 1-palmitoyl-2-[8-[3(5-octyl-1,2,4-trioxolan-3-yl)octanoyl]--sn-gly cero-3- phosphocholine (PC-Criegee ozonide) and 1-palmitoyl-2-(9...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx00039a026

    authors: Salgo MG,Squadrito GL,Pryor WA

    更新日期:1994-05-01 00:00:00

  • Genotoxicity evaluation of nanomaterials: dna damage, micronuclei, and 8-hydroxy-2-deoxyguanosine induced by magnetic doped CdSe quantum dots in male mice.

    abstract::Quantum dots (QDs) are a novel class of inorganic fluorophores which are gaining widespread recognition as a result of their exceptional photophysical properties and their applications as a biomarker and in molecular biomedical imaging. The aim of this study was to evaluate the in vivo genotoxicity in mice exposed to ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx2000015

    authors: Khalil WK,Girgis E,Emam AN,Mohamed MB,Rao KV

    更新日期:2011-05-16 00:00:00

  • Base sequence-dependent bends in site-specific benzo[a]pyrene diol epoxide-modified oligonucleotide duplexes.

    abstract::The site specifically modified oligonucleotides 5'-d(TCCTCCTG1G2CCTCTC) (I) and 5'-d(CTATG1G2G3TATC) (II) were synthesized with single modified guanine residues at positions G1, G2, or G3, derived from the covalent binding reaction of 7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene ((+)-anti-BPDE) with ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx9501086

    authors: Liu T,Xu J,Tsao H,Li B,Xu R,Yang C,Amin S,Moriya M,Geacintov NE

    更新日期:1996-01-01 00:00:00

  • Decomposition and quality control considerations in biological work with fecapentaene preparations.

    abstract::Solutions of synthetic fecapentaene 12 (FP-12) intended for carcinogenicity studies were found to decompose extremely rapidly during customary dosage procedures. Apparent half-lives as short as 15 min were observed. While rates and even the qualitative course of decomposition were surprisingly variable in replicate ex...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx00009a007

    authors: Streeter AJ,Donovan PJ,Anjo T,Ohannesian L,Sheffels PR,Wu PP,Keefer LK,Andrews AW,Bradford WW 3rd,Reist EJ

    更新日期:1989-05-01 00:00:00

  • Human liver microsomal cytochrome P450 3A enzymes involved in thalidomide 5-hydroxylation and formation of a glutathione conjugate.

    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

    authors: Chowdhury G,Murayama N,Okada Y,Uno Y,Shimizu M,Shibata N,Guengerich FP,Yamazaki H

    更新日期:2010-06-21 00:00:00

  • Mapping serum albumin adducts of the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by data-dependent tandem mass spectrometry.

    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

    authors: Peng L,Dasari S,Tabb DL,Turesky RJ

    更新日期:2012-10-15 00:00:00

  • Nontoxic and neuroprotective β-naphthotacrines for Alzheimer's disease.

    abstract::The synthesis, toxicity, neuroprotection, and human acetylcholinesterase (hAChE)/ human butyrylcholinesterase (hBuChE) inhibition properties of β-naphthotacrines1-14 as new drugs for Alzheimer's disease (AD) potential treatment, are reported. β-Naphthotacrines1-14 showed lower toxicity than tacrine; moreover, at the h...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx400138s

    authors: Esquivias-Pérez M,Maalej E,Romero A,Chabchoub F,Samadi A,Marco-Contelles J,Oset-Gasque MJ

    更新日期:2013-06-17 00:00:00

  • DNA Polymerases η and ζ Combine to Bypass O(2)-[4-(3-Pyridyl)-4-oxobutyl]thymine, a DNA Adduct Formed from Tobacco Carcinogens.

    abstract::4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are important human carcinogens in tobacco products. They are metabolized to produce a variety 4-(3-pyridyl)-4-oxobutyl (POB) DNA adducts including O(2)-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine (O(2)-POB-dT), the most abundant POB adduc...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/acs.chemrestox.5b00468

    authors: Gowda AS,Spratt TE

    更新日期:2016-03-21 00:00:00

  • Pharmacodynamics of cytochrome P450 2B induction by phenobarbital, 5-ethyl-5-phenylhydantoin, and 5-ethyl-5-phenyloxazolidinedione in the male rat liver or in cultured rat hepatocytes.

    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

    authors: Nims RW,Sinclair PR,Sinclair JF,Thomas PE,Jones CR,Mellini DW,Syi JL,Lubet RA

    更新日期:1993-03-01 00:00:00

  • Tobacco-specific nitrosamine-derived O2-alkylthymidines are potent mutagenic lesions in SOS-induced Escherichia coli.

    abstract::To investigate the biological effects of the O(2)-alkylthymidines induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), we have replicated a plasmid containing O(2)-methylthymidine (O(2)-Me-dT) or O(2)-[4-(3-pyridyl-4-oxobut-1-yl]thymidine (O(2)-POB-dT) in Escherichia coli w...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx200435d

    authors: Jasti VP,Spratt TE,Basu AK

    更新日期:2011-11-21 00:00:00

  • Structure-toxicity relationships for the effects to Tetrahymena pyriformis of aliphatic, carbonyl-containing, alpha,beta-unsaturated chemicals.

    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

    authors: Schultz TW,Netzeva TI,Roberts DW,Cronin MT

    更新日期:2005-02-01 00:00:00

  • Notopterygium forbesii boiss extract and its active constituents increase reactive species and heme oxygenase-1 in human fetal hepatocytes: mechanisms of action.

    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

    authors: Tang SY,Wang H,Zhang W,Halliwell B

    更新日期:2008-12-01 00:00:00

  • Hydrolytic Cleavage Products of Globin Adducts in Urine as Possible Biomarkers of Cumulative Dose: Proof of Concept Using Styrene Oxide as a Model Adduct-Forming Compound.

    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

    authors: Mráz J,Hanzlíková I,Moulisová A,Dušková Š,Hejl K,Bednářová A,Dabrowská L,Linhart I

    更新日期:2016-04-18 00:00:00

  • Polychlorinated Biphenyl Quinone Induces Caspase 1-Mediated Pyroptosis through Induction of Pro-inflammatory HMGB1-TLR4-NLRP3-GSDMD Signal Axis.

    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

    authors: Dong W,Zhu Q,Yang B,Qin Q,Wang Y,Xia X,Zhu X,Liu Z,Song E,Song Y

    更新日期:2019-06-17 00:00:00

  • Hydroxywarfarin metabolites potently inhibit CYP2C9 metabolism of S-warfarin.

    abstract::Coumadin (R/S-warfarin) anticoagulant therapy poses a risk to over 50 million Americans, in part due to interpersonal variation in drug metabolism. Consequently, it is important to understand how metabolic capacity is influenced among patients. Cytochrome P450s (P450 or CYP for a specific isoform) catalyze the first m...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx1000283

    authors: Jones DR,Kim SY,Guderyon M,Yun CH,Moran JH,Miller GP

    更新日期:2010-05-17 00:00:00

  • Stability and reactivity of 2-nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline.

    abstract::2-Nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-NO-MeIQx) is a nitrosation product of the food carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and is proposed to form in vivo under inflammatory conditions. This study evaluated the stability and reactivity of N-NO-MeIQx to assess its possible r...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx050305x

    authors: Lakshmi VM,Hsu FF,Schut HA,Zenser TV

    更新日期:2006-02-01 00:00:00

  • Reactions of the Zn Proteome with Cd2+ and Other Xenobiotics: Trafficking and Toxicity.

    abstract::Understanding the molecular basis of inorganic chemical toxicity has lagged behind the proliferation of detailed mechanisms that explain the biochemical toxicology of many organic xenobiotics. In this perspective, general barriers to explicating the bioinorganic chemistry of toxic metals are considered, followed by a ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/acs.chemrestox.6b00328

    authors: Petering DH

    更新日期:2017-01-17 00:00:00

  • Evaluating the Cytotoxicity of Ti3C2 MXene to Neural Stem Cells.

    abstract::MXenes have attracted extensive attention due to their unique physicochemical properties. Especially, the flexibility and good conductivity endow MXenes with a great application prospect in the neural interfaces. However, the cytotoxicity of MXenes to nervous system remains unclear. In this study, we evaluated the cyt...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/acs.chemrestox.0c00232

    authors: Wu W,Ge H,Zhang L,Lei X,Yang Y,Fu Y,Feng H

    更新日期:2020-12-21 00:00:00

  • Metabolomic characterization of laborers exposed to welding fumes.

    abstract::The complex composition of welding fumes, multiplicity of molecular targets, diverse cellular effects, and lifestyles associated with laborers vastly complicate the assessment of welding fume exposure. The urinary metabolomic profiles of 35 male welders and 16 male office workers at a Taiwanese shipyard were character...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx200465e

    authors: Wang KC,Kuo CH,Tian TF,Tsai MH,Chiung YM,Hsiech CM,Tsai SJ,Wang SY,Tsai DM,Huang CC,Tseng YJ

    更新日期:2012-03-19 00:00:00

  • Lysine Adduction by Reactive Metabolite(s) of Monocrotaline.

    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

    authors: Li W,Wang K,Lin G,Peng Y,Zheng J

    更新日期:2016-03-21 00:00:00

  • Cytochrome P450 2A5 constitutive expression and induction by heavy metals is dependent on redox-sensitive transcription factor Nrf2 in liver.

    abstract::Mouse cytochrome P450 2A5 (CYP2A5) is upregulated in various pathophysiological liver diseases and induced by structurally variable hepatotoxic chemicals. A putative common feature for all of these conditions is altered cellular redox status. Nuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor that is p...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx100084c

    authors: Lämsä V,Levonen AL,Leinonen H,Ylä-Herttuala S,Yamamoto M,Hakkola J

    更新日期:2010-05-17 00:00:00

  • Internalization of carbon black and maghemite iron oxide nanoparticle mixtures leads to oxidant production.

    abstract::The risk of potential human exposure to mixed nanomaterials in consumer, occupational, and medicinal settings is increasing as nanomaterials enter both the workplace and the marketplace. In this study, we investigated the toxicity of mixed engineered carbon black (ECB) and maghemite iron oxide (Fe(2)O(3)) nanoparticle...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx100307h

    authors: Berg JM,Ho S,Hwang W,Zebda R,Cummins K,Soriaga MP,Taylor R,Guo B,Sayes CM

    更新日期:2010-12-20 00:00:00

  • Use of Zebrafish in Drug Discovery Toxicology.

    abstract::Unpredicted human safety events in clinical trials for new drugs are costly in terms of human health and money. The drug discovery industry attempts to minimize those events with diligent preclinical safety testing. Current standard practices are good at preventing toxic compounds from being tested in the clinic; howe...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章,评审

    doi:10.1021/acs.chemrestox.9b00335

    authors: Cassar S,Adatto I,Freeman JL,Gamse JT,Iturria I,Lawrence C,Muriana A,Peterson RT,Van Cruchten S,Zon LI

    更新日期:2020-01-21 00:00:00