Abstract:
:Adverse effects of drugs (AEDs) continue to be a major cause of drug withdrawals in both development and postmarketing. While liver-related AEDs are a major concern for drug safety, there are few in silico models for predicting human liver toxicity for drug candidates. We have applied the quantitative structure-activity relationship (QSAR) approach to model liver AEDs. In this study, we aimed to construct a QSAR model capable of binary classification (active vs inactive) of drugs for liver AEDs based on chemical structure. To build QSAR models, we have employed an FDA spontaneous reporting database of human liver AEDs (elevations in activity of serum liver enzymes), which contains data on approximately 500 approved drugs. Approximately 200 compounds with wide clinical data coverage, structural similarity, and balanced (40/60) active/inactive ratios were selected for modeling and divided into multiple training/test and external validation sets. QSAR models were developed using the k nearest neighbor method and validated using external data sets. Models with high sensitivity (>73%) and specificity (>94%) for the prediction of liver AEDs in external validation sets were developed. To test applicability of the models, three chemical databases (World Drug Index, Prestwick Chemical Library, and Biowisdom Liver Intelligence Module) were screened in silico, and the validity of predictions was determined, where possible, by comparing model-based classification with assertions in publicly available literature. Validated QSAR models of liver AEDs based on the data from the FDA spontaneous reporting system can be employed as sensitive and specific predictors of AEDs in preclinical screening of drug candidates for potential hepatotoxicity in humans.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Rodgers AD,Zhu H,Fourches D,Rusyn I,Tropsha Adoi
10.1021/tx900451rsubject
Has Abstractpub_date
2010-04-19 00:00:00pages
724-32issue
4eissn
0893-228Xissn
1520-5010journal_volume
23pub_type
杂志文章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::Oxidized nucleobases represent one of the main classes of damage induced in DNA by ionizing radiation. Emphasis was placed in this work on the measurement of four oxidized pyrimidine bases, including 5-(hydroxymethyl)uracil (5-HMUra), 5-formyluracil (5-ForUra), 5-hydroxycytosine (5-OHCyt), and 5-hydroxyuracil (5-OHUra...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960095b
更新日期:1996-10-01 00:00:00
abstract::Little is known about the formation and disposition of benzene oxide (BO), the initial metabolite arising from oxidation of benzene by cytochrome P450. In this study, reactions of BO with hemoglobin (Hb) and albumin (Alb) were investigated in blood from B6C3F1 mice, F344 rats, and humans in vitro. The estimated half-l...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx9701788
更新日期:1998-04-01 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::3-Chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone (CMCF) is a strong direct acting bacterial mutagen found in chlorine-disinfected drinking water. We studied the reaction of CMCF with 2-deoxyadenosine in buffered aqueous solutions and found that three main adducts were formed. The adducts were isolated and purified b...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx990116c
更新日期:1999-12-01 00:00:00
abstract::As metals are ubiquitous in the environment, humans are continuously exposed to them. Although some metallic ions play key roles in human physiology, most metals are redundant and are actually hazardous to humans. A frequent event in the toxicological cascade triggered by nonessential metals concerns the abrogation of...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx100276f
更新日期:2010-12-20 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::Skin sensitizers chemically modify skin proteins rendering them immunogenic. Sensitizing chemicals have been divided into applicability domains according to their suspected reaction mechanism. The widely accepted Schiff base applicability domain covers aldehydes and ketones, and detailed structure-activity-modeling fo...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300278t
更新日期:2012-10-15 00:00:00
abstract::In a recent study, we reported that interleukin (IL)-4 had a protective role against acetaminophen (APAP)-induced liver injury (AILI), although the mechanism of protection was unclear. Here, we carried out more detailed investigations and have shown that one way IL-4 may control the severity of AILI is by regulating g...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx2003992
更新日期:2012-01-13 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::Glutathione peroxidases and their mimics, e.g., ebselen or diaryl tellurides, efficiently reduce peroxynitrite/peroxynitrous acid (ONOO-/ONOOH) to nitrite and protect against oxidation and nitration reactions. Here, we report the second-order rate constant for the reaction of the reduced form of glutathione peroxidase...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx980086y
更新日期:1998-12-01 00:00:00
abstract::Aflatoxin Q1 8,9-oxide was synthesized and found to yield lower levels of N7-guanyl adducts than obtained from aflatoxin B1 8,9-oxide when mixed with calf thymus DNA or Salmonella typhimurium TA 98 cells. However, when S. typhimurium TA 98 was treated with the (analogous) epoxides of aflatoxin B1, aflatoxin G1, aflato...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00026a009
更新日期:1992-03-01 00:00:00
abstract::Radionuclides represent a serious health risk to humans in the case of incorporation. To elucidate the potential of time-resolved laser-induced fluorescence spectroscopy (TRLFS) to determine the dominant radionuclide species in natural biofluids, we investigated the in vitro speciation of curium(III) in human urine sa...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx100273g
更新日期:2011-02-18 00:00:00
abstract::The antitumor agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) is known to be unstable in aqueous solution, and to degrade spontaneously to reactive alkylating and carbamoylating intermediates. Whereas the alkylating component is believed to be responsible for the antitumor effects of this drug, it has been speculat...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00033a020
更新日期:1993-05-01 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::Formyl chloride has been indirectly implicated as an intermediate in the oxidation of CH(2)Cl(2) and proposed to be a product of the oxidation of some other compounds. Formyl chloride was synthesized and added to aqueous solutions, with CO formed as a product. The presence of glutathione (GSH) did not reduce the yield...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx060087n
更新日期:2006-08-01 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::Finger 3 of transcription factor IIIA of Xenopus laevis was synthesized and constituted with Zn(2+) or Cd(2+). The C-block element of the internal control region of the promoter of the 5S rRNA gene binds to the Zn-F3 and Cd-F3 with dissociation constants of 2.6 x 10(-5) and 1.5 x 10(-4) M, respectively. According to N...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx030057+
更新日期:2004-07-01 00:00:00
abstract::The .CCl3 radical generated during the metabolism of CCl4 is readily spin trapped in vivo and in vitro by phenyl N-tert-butylnitrone (PBN) to form the stable PBN/.CCl3 radical adduct, which can then be extracted into organic solvents and detected by ESR spectroscopy. We have used this technique to examine the proposed...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00035a017
更新日期:1993-09-01 00:00:00
abstract::Diastereomeric 8,5'-cyclopurine 2'-deoxynucleosides, containing a covalent bond between the deoxyribose and the purine base, are induced in DNA by ionizing radiation. They are suspected to play a role in the etiology of neurodegeneration in xeroderma pigmentosum patients. If not repaired, the S-8,5'-cyclo-2'-deoxyguan...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx2005053
更新日期:2012-02-20 00:00:00
abstract::It is vital that methylated trivalent arsenicals [MA(III) and DMA(III)] are described and characterized unequivocally due to their high toxicity. Two different ways of generating the methylated trivalent arsenicals have been practiced-reduction of the methylated pentavalent arsenical either by the sodium-metabisulfite...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx049978q
更新日期:2004-08-01 00:00:00
abstract::Both cooked red meat intake and chronic inflammation/infection are thought to play a role in the etiology of colon cancer. The heterocyclic amine 2-amino-3-methylimidazo[4,5-f ]quinoline (IQ) is formed during cooking of red meat and may be involved in initiation of colon cancer. Reactive nitrogen oxygen species (RNOS)...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx020008h
更新日期:2002-08-01 00:00:00
abstract::The purpose of this study was to investigate the degree of chlorination of catechol (CAT) derivatives of pentachlorophenol (PCP) on the induction of cytotoxicity and DNA damaging effects in calf thymus DNA (ct-DNA) and in two human breast carcinoma cell lines. Results indicated that with the addition of the transition...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0498511
更新日期:2005-02-01 00:00:00
abstract::Peroxynitrite (PN), a very reactive oxidant formed by the combination of superoxide and nitric oxide, appears to play a role in producing tissue damage in a number of inflammatory conditions. Pharmacological scavenging and decomposition of PN within these areas has therapeutic value in several tissue injury models. Re...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx990159t
更新日期:2000-04-01 00:00:00
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
更新日期:2017-01-17 00:00:00
abstract::Thiacetazone (TAZ) and ethionamide (ETA) are, respectively, thiourea- and thioamide-containing second line antitubercular prodrugs for which there is an extensive clinical history of cross-resistance in Mycobacterium tuberculosis. EtaA, a recently identified flavin-containing monooxygenase (FMO), is responsible for th...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050328b
更新日期:2006-03-01 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::2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 1-nitropyrene (1-NP), and benzo[a]pyrene (BaP) are toxic environmental pollutants. TCDD was shown to suppress p53 expression in response to genotoxic stress and hypoxic conditions. However, the mechanism of TCDD's actions is not clearly understood. Our data showed that pretr...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200309p
更新日期:2011-12-19 00:00:00
abstract::The hepatic metabolism of microcystins (MCs), potent cyclic peptide hepatotoxins produced by cyanobacteria, was studied by i.p. injection in mice and rats. An immunoaffinity purification method using an anti-MC-LR monoclonal antibody showed a remarkable effect on the removal of contaminants in the hepatic cytosol and ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960085a
更新日期:1996-12-01 00:00:00
abstract::Although many phenols and catechols found as polyphenol natural products are antioxidants and have putative disease-preventive properties, others have deleterious health effects. One possible route to toxicity is the bioactivation of the phenolic function to quinones that are electrophilic, redox-agents capable of mod...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200140s
更新日期:2011-09-19 00:00:00