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, the corresponding chemical instability, toxic potential, and low bioavailability of these compounds could limit their ultimate clinical relevance. We have shown that pharmacophores of curcumin (e.g., 2-acetylcyclopentanone) and phloretin (e.g., 2',4',6'-trihydroxyacetophenone; THA) can provide cytoprotection in cell culture and animal models of oxidative stress injury. These pharmacophores are 1,3-dicarbonyl and polyphenol derivatives, the enol groups of which can ionize in biological solutions to form an enolate. This carbanionic moiety can chelate metal ions and, as a nucleophile, can scavenge toxic electrophiles (e.g., acrolein, 4-hydroxy-2-nonenal, and N-acetyl-p-benzoquinone imine) involved in many pathogenic conditions. Aromatic derivatives such as THA can also trap free oxygen and nitrogen radicals and thereby provide another layer of cytoprotection. The multifunctional character of these enolate-forming compounds suggests an ability to block pathogenic processes (e.g., oxidative stress) at several steps. The purpose of this review is to discuss research supporting our theory that enolate formation is a significant cytoprotective property that represents a platform for development of pharmacotherapeutic approaches to a variety of toxic and pathogenic conditions. Our discussion will focus on mechanism and structure-activity studies that define enolate chemistry and their corresponding relationships to cytoprotection.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
LoPachin RM,Geohagen BC,Nordstrøm LU,Gavin Tdoi
10.1021/acs.chemrestox.6b00300subject
Has Abstractpub_date
2016-12-19 00:00:00pages
2096-2107issue
12eissn
0893-228Xissn
1520-5010journal_volume
29pub_type
杂志文章,评审abstract：:The reaction of the antitumor agent leinamycin with thiols converts this natural product into an episulfonium ion that alkylates the N7-position of guanine residues in double-stranded DNA. It is reported here that depurination of this adduct is unusually facile, occurring with a half-life of about 3.5 h at pH 7 and 37...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx049964k
更新日期：2004-07-01 00:00:00
abstract：:1-{4-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]benzyl}azetidine-3-carboxylic acid (MRL-A) is a potent sphingosine-1-phosphate-1 receptor agonist, with potential application as an immunosuppressant in organ transplantation or for the treatment of autoimmune diseases. When administered orally to rats, radiolabeled ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx300017s
更新日期：2012-07-16 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：:Estrogen replacement therapy has been correlated with an increased risk of developing breast or endometrial cancer. 4-Hydroxyequilenin (4-OHEN) is a catechol metabolite of equilenin which is a minor component of the estrogen replacement formulation marketed under the name of Premarin (Wyeth-Ayerst). Previously, we sho...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx990186j
更新日期：2000-05-01 00:00:00
abstract：:Chromium(III) tris(picolinate) [Cr(pic)3] is currently a very popular nutritional supplement; however, its safety has recently been questioned, especially with regard to its ability to act as a clastogen. At physiologically relevant concentrations, Cr(pic)3 is reduced by biological reductants, including ascorbate and ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx9900167
更新日期：1999-06-01 00:00:00
abstract：:Inorganic arsenic is a strong carcinogen, possibly by interaction with the telomere length. The aim of the study was to evaluate how chronic arsenic exposure from drinking water as well as the arsenic metabolism efficiency affect the individual telomere length and the expression of telomere-related genes. Two hundred ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx300222t
更新日期：2012-11-19 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：:The primary products of one-electron oxidation of clozapine and olanzapine, very effective atypical antipsychotic drugs, have been spectroscopically characterized. The oxidation process has been studied under glassy matrix conditions and by a pulse radiolysis technique in aqueous solution. The rate constants for the o...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx700128c
更新日期：2007-08-01 00:00:00
abstract：:Exposure to fine particulate matter (PM2.5), of which secondary organic aerosol (SOA) is a major constituent, is linked to adverse health outcomes, including cardiovascular disease, lung cancer, and preterm birth. Atmospheric oxidation of isoprene, the most abundant nonmethane hydrocarbon emitted into Earth's atmosphe...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.9b00322
更新日期：2020-02-17 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx970201p
更新日期：1998-05-01 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：: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
abstract：:The genotoxicity of the dihydrofurans aflatoxin B1 (AFB1), aflatoxin G1 (AFG1), and sterigmatocystin (STG) was examined in a bacterial system in which the induction of SOS repair is monitored with the umuC gene linked to a lacZ reporter gene in plasmid pSK1002. Human liver microsomal cytochrome P-450NF oxidized the di...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00008a008
更新日期：1989-03-01 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
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：:Chlorophyllin (CHL), a food-grade derivative of the green plant pigment chlorophyll, has recently been shown in this laboratory to be a potent inhibitor in vivo of hepatic aflatoxin B1 (AFB1)-DNA adduction and hepatocarcinogenesis (Breinholt et al. (1995) Cancer Res. 55, 57-62). We report here that CHL forms a strong ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00046a004
更新日期：1995-06-01 00:00:00
abstract：:The 1-octanol/water partition coefficients of a number of toxic and nontoxic analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were determined using centrifugal partition chromatography (CPC), a novel and effective technique for measuring lipophilicity, and found to be highly correlated with values calc...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00027a008
更新日期：1992-05-01 00:00:00
abstract：:Nucleotide excision repair (NER) removes lesions caused by environmental mutagens or UV light from DNA. A hallmark of NER is the extraordinarily wide substrate specificity, raising the question of how one set of proteins is able to recognize structurally diverse lesions. Two key features of good NER substrates are tha...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx3003033
更新日期：2012-11-19 00:00:00
abstract：:The ToxCast EPA challenge was managed by TopCoder in Spring 2014. The goal of the challenge was to develop a model to predict the lowest effect level (LEL) concentration based on in vitro measurements and calculated in silico descriptors. This article summarizes the computational steps used to develop the Rank-I model...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.5b00481
更新日期：2016-05-16 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx700168z
更新日期：2007-09-01 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.9b00506
更新日期：2020-04-20 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx0002278
更新日期：2001-04-01 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx400138s
更新日期：2013-06-17 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx500416y
更新日期：2015-05-18 00:00:00
abstract：:Cytochrome P450 enzymes (CYPs) metabolize alkyl- and arylamines, generating several different products. For the primary and secondary amines, some of these reactions result in hydroxylated amines, which may be toxic. Thus, when designing new drugs containing amine groups, it is important to be able to predict if a giv...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx500371a
更新日期：2015-04-20 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx049821y
更新日期：2004-12-01 00:00:00
abstract：:Allyl alcohol (AA) is one of the environmental pollutants used as a herbicide and industrial chemical. AA undergoes enzymatic oxidation in vivo to form Acrolein (Acr), a highly reactive and ubiquitous environmental toxicant. The exposure to AA/Acr has detrimental effects on cells and is highly fatal. In corroboration ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.5b00071
更新日期：2015-06-15 00:00:00
abstract：:Cancer-associated mutations often lead to perturbed cellular energy metabolism and accumulation of potentially harmful oncometabolites. One example is the chiral molecule 2-hydroxyglutarate (2HG); its two stereoisomers (d- and l-2HG) have been found at abnormally high concentrations in tumors featuring anomalous metab...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.7b00009
更新日期：2017-04-17 00:00:00
abstract：:Two hemorrhagic proteases, Lachesis hemorrhagic toxins a and b (LHTa and LHTb), were isolated from the venom of Lachesis muta, which is distributed in Central and South America. One protease showed strong hemorrhagic action, while the other showed weak hemorrhagic activity even though the two enzymes are very similar ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00006a003
更新日期：1988-11-01 00:00:00
abstract：:Skin protein modification (haptenation) is thought to be a key step in the manifestation of sensitization to low molecular mass chemicals (<500 g/mol). For sensitizing chemicals that are not protein reactive, it is hypothesised that metabolic activation can convert such chemicals into protein reactive toxins within th...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx0341456
更新日期：2004-03-01 00:00:00
