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 causative agents for this hepatotoxicity. However, no experimental information is available at the molecular level on the possible role of NQO1 in the detoxification of EGCG and its metabolites, including reactive intermediates. In the present study, we investigated the possibility of NQO1 inhibition by EGCG and its metabolites by studying their interaction profiles and binding mechanism at the active site of NQO1 using molecular docking, binding free energy calculations, and molecular dynamics (MD) simulations. The binding free energy calculations showed that some metabolites exhibited strong predicted binding affinity and found that the binding orientation of the EGCG metabolites overlapped with that of dicoumarol found in an NQO1 X-ray crystal structure. The results suggest that these metabolites may act as strong NQO1 inhibitors, highlighting the need for experimental validation of this with appropriate biological methods. The Prime MM-GBSA computed average binding free energies after MD simulations of compounds 1, 2, 24, 31, and 33 revealed that these compounds highly favored van der Waals (VdW) and Coulombic interactions with NQO1. In addition, the MD results revealed that selected EGCG metabolites formed a stable and strong complex with NQO1, with amino acids W105, Y126, Y128, H161, F178, H194, F232, and F236 being critical for potential NQO1 binding. The current results together with experimental data as well as studies of the polymorphisms of NQO1 (especially C609T) may explain the observed idiosyncratic hepatotoxicity caused by the consumption of green tea and its constituents.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Pandey P,Avula B,Khan IA,Khan SI,Navarro VJ,Doerksen RJ,Chittiboyina AGdoi
10.1021/acs.chemrestox.9b00450subject
Has Abstractpub_date
2020-11-16 00:00:00pages
2749-2764issue
11eissn
0893-228Xissn
1520-5010journal_volume
33pub_type
杂志文章abstract::The preparation and DNA binding characteristics of a structural analog of Hoechst 33258 bearing two pyridinic nitrogen atoms are described. The 1H NMR signals of the complex formed between the new ligand 1 and decadeoxyribonucleotide d(CATGGCCATG)2 were assigned by employing one- and two-dimensional NMR techniques. In...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00029a003
更新日期:1992-09-01 00:00:00
abstract::Faithful replication of DNA is a critical aspect in maintaining genome integrity. DNA polymerases are responsible for replicating DNA, and high-fidelity polymerases do this rapidly and at low error rates. Upon exposure to exogenous or endogenous substances, DNA can become damaged and this can alter the speed and fidel...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/acs.chemrestox.7b00224
更新日期:2017-11-20 00:00:00
abstract::Alcohol consumption is associated with an increased risk of several types of malignancy by mechanisms that remain to be elucidated. Most of the ingested ethanol is converted to acetaldehyde but the formation of free radical metabolites such as the 1-hydroxyethyl radical has been also demonstrated to occur in vitro and...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx9800351
更新日期:1998-08-01 00:00:00
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 reactiv...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx600332p
更新日期:2007-04-01 00:00:00
abstract::Chemical respiratory sensitization is an immunological process that manifests clinically mostly as occupational asthma and is responsible for 1 in 6 cases of adult asthma, although this may be an underestimate of the prevalence, as it is under-diagnosed. Occupational asthma results in unemployment for roughly one-thir...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00320
更新日期:2020-12-15 00:00:00
abstract::The conjugation of reactive drug metabolites to GSH is considered an important detoxification mechanism that can be spontaneous and/or mediated by glutathione S-transferases (GSTs). In case GSTs play an important role in GSH conjugation, genetically determined deficiencies in GSTs may be a risk factor for adverse drug...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx100131f
更新日期:2010-09-20 00:00:00
abstract::The role of prostaglandin H synthase-1 (PHS-1) and a related model enzyme, horseradish peroxidase (HRP), in catalyzing the bioactivation of dopamine (DA) and epinephrine and their precursors and metabolites to potential neurodegenerative free radical intermediates was examined. To determine the potential contribution ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800423s
更新日期:2009-05-01 00:00:00
abstract::Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly population, above 65 years of age. Multiple lines of evidence confirm the central role of 40-42 residue Abeta peptides in the pathogenesis of AD, but exact mechanisms of Abeta toxicity remain unclear. Recently, evidence has accumulat...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx900358j
更新日期:2010-02-15 00:00:00
abstract::The metabolic pathway of tetrodotoxin (TTX), a powerful and specific voltage-gated sodium channel blocker, has not been well-clarified either in TTX-poisoned patients or in puffer fish. 4-S-CysteinylTTX (4-CysTTX) was isolated from the liver of the puffer fish, Fugu pardalis, as the first adduct of TTX with thiol. The...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050015g
更新日期:2005-05-01 00:00:00
abstract::4-Hydroxy-2-nonenal (HNE), a major electrophilic byproduct of lipid peroxidation, is mutagenic and cytotoxic. The two pairs of HNE-derived diastereomeric 1,N2-propanodeoxyguanosine 3'-monophosphate adducts were synthesized from reaction of HNE with 2'-deoxyguanosine 3'-monophosphate. After HPLC separation, these adduc...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx970100r
更新日期:1997-11-01 00:00:00
abstract::The conformation of the crotonaldehyde-derived N(2)-[3-oxo-1(S)-methyl-propyl]-dG adduct in the oligodeoxynucleotide 5'-d(G(1)C(2)T(3)A(4)G(5)C(6)X(7)A(8)G(9)T(10)C(11)C(12))-3'.5'-d(G(13)G(14)A(15)C(16)T(17)C(18)G(19)C(20)T(21)A(22)G(23)C(2)(4))-3', where X = N(2)-[3-oxo-1(S)-methyl-propyl]-dG, is reported. This addu...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0600604
更新日期:2006-08-01 00:00:00
abstract::Epidemiological studies have implicated a role for airborne particulates of <2.5 microm diameter in the development/exacerbation of chronic cardiopulmonary disease; however, specific pathogenic mechanisms and the etiological significance of particle physicochemical properties remain unresolved. Using a microporous alu...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx049893p
更新日期:2004-10-01 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::The mechanism of DNA adduct formation by acroleins substituted with good leaving groups in the beta-position was investigated using [3-2H]-3-(p-nitrophenoxy)acrolein (1). Reaction of 1 with guanosine at acidic pH produced 9-beta-D-ribofuranosylpyrimido[1,2-alpha]purin-10(3H)-one containing equal amounts of deuterium a...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx950105t
更新日期:1996-01-01 00:00:00
abstract::Depleted uranium (DU) is commonly used in military armor and munitions, and thus, exposure of soldiers and non-combatants is potentially frequent and widespread. DU is considered a suspected human carcinogen, affecting the bronchial cells of the lung. However, few investigations have studied DU in human bronchial cell...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx700026r
更新日期:2007-05-01 00:00:00
abstract::Thiol conjugates of isothiocyanates (thiol-ITCs) are metabolites of ITCs formed in the mercapturic acid pathway in mammals. They are effective chemopreventive agents in mouse lung tumor bioassays and in other models. Thiol-ITCs are inhibitors of P450s, but it has not been determined if P450 inhibition is due to conjug...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx010029w
更新日期:2001-09-01 00:00:00
abstract::Oxidation of the tris(p-carboxyltetrathiaaryl)methyl (TAM) EPR radical probe, TAMa(•), by rat liver microsomes (RLM) + NADPH, or horseradish peroxidase (HRP) + H2O2, or K2IrCl6, led to an intermediate cation, TAMa(+), which was treated with glutathione (GSH), with formation of an adduct, TAMa-SG(•), resulting from the...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400467p
更新日期:2014-04-21 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::Estrogens can have two roles in the induction of cancer: stimulating proliferation of cells by receptor-mediated processes, and generating electrophilic species that can covalently bind to DNA. The latter role is thought to proceed through catechol estrogen metabolites, which can be oxidized to o-quinones that bind to...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960002q
更新日期:1996-07-01 00:00:00
abstract::Premarin (Wyeth-Ayerst) is the estrogen replacement treatment of choice and continues to be one of the most widely dispensed prescriptions in the United States. In addition to endogenous estrogens, Premarin contains unsaturated estrogens including equilenin. We synthesized the catechol metabolite of equilenin, 4-hydro...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx970181r
更新日期:1998-02-01 00:00:00
abstract::NADPH in microsomes reduces the hydroxocob(III)alamin form of vitamin B12 to cob(II)alamin and the supernucleophilic cob(I)alamin, which are both highly reactive toward xenobiotic epoxides formed by mammalian metabolism of dienes such as the industrially important chemicals chloroprene and 1,3-butadiene. With styrene,...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0497898
更新日期:2004-12-01 00:00:00
abstract::We propose here a combined gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) metabolic profiling strategy to elucidate the toxicity in rats induced by orally administered multiglycosides of Tripterygium wilfordii Hook. f. (GTW) in multiple organs including the kidney, liv...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx7002905
更新日期:2008-02-01 00:00:00
abstract::3'-Hydroxyacetanilide (AMAP) is a nonhepatotoxic regioisomer of acetaminophen (APAP) that nonetheless does form reactive metabolites which bind to hepatic proteins. Because differences in the nature of reactive metabolites formed from AMAP and APAP may explain differences in their propensity to cause hepatotoxicity, c...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00007a007
更新日期:1989-01-01 00:00:00
abstract::In this study, human glutathione transferases (GSTs) of alpha class have been assayed with the ultimate carcinogenic (-)-anti- and (+)-syn-diol epoxides (DEs) derived from the nonplanar dibenzo[a,l]pyrene (DBPDE) and the (+)-anti-diol epoxide of the planar benzo[a]pyrene [(+)-anti-BPDE] in the presence of glutathione ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx025519i
更新日期:2002-06-01 00:00:00
abstract::Quantitation of DNA adducts could provide critical information on the relationship between exposure to tobacco smoke and cancer risk in smokers. In this study, we developed a robust and sensitive liquid chromatography-tandem mass spectrometry method for the analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasin...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300282k
更新日期:2013-01-18 00:00:00
abstract::Today much is known about cytochrome P450 (P450) enzymes and their catalytic specificity, but the range of reactions catalyzed by each still continues to surprise. Historically, P450s had been considered to be involved in either the metabolism of xenobiotics or endogenous chemicals, in the former case playing a genera...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.6b00226
更新日期:2017-01-17 00:00:00
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
更新日期:2008-07-01 00:00:00
abstract::The hepatotoxicity of Troglitazone (TGZ) has been ascribed to the formation of reactive metabolites, and the primary reactive metabolite of TGZ has been confirmed to be an o-quinone methide. Oxidation of the chromane moiety is also known to produce quinone containing metabolites. Quantum chemical studies have been per...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200110h
更新日期:2011-07-18 00:00:00
abstract::Nicking of the DNA strand immediately upstream of an internal abasic (AP) site produces 5'-terminal abasic (dRp) DNA. Both the intact and the nicked abasic species are reactive intermediates along the DNA base excision repair (BER) pathway and can be derailed by side reactions. Aberrant accumulation of the 5'-terminal...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.7b00057
更新日期:2017-06-19 00:00:00
abstract::The synthesis of the 8 possible stereoisomeric diol epoxides (DEs) at the terminal benzo ring of carcinogenic dibenz[a,h]anthracene (DBA) is reported. trans-3,4-Dihydroxy-3,4-dihydro-DBA (1) afforded the 4 bay region DEs: the enantiomeric pairs of the anti diastereomers (+)-3/(-)-3 and of the syn diastereomers (-)-4/(...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200398b
更新日期:2011-12-19 00:00:00