Abstract：
:Drug-induced kidney injury (DIKI) is a common toxicity observed in pharmaceutical development. We demonstrated the use of label-free liquid chromatography-mass spectrometry (LC-MS) and multiplex liquid chromatography-single reaction monitoring (LC-SRM) as practical extensions of standard immunoassay based safety biomarker assessments for identification of new toxicity marker candidates and for improved mechanistic understanding. Two different anticancer drugs, doxorubicin (DOX) and cisplatin (cis-diamminedichloridoplatinum, CDDP), were chosen as the toxicants due to their different modes of nephrotoxicity. Analyses of urine samples from toxicant treated and untreated rats were compared to identify biochemical analytes that changed in response to toxicant exposure. A discovery (label-free LC-MS) and targeted proteomics (multiplex LC-SRM) approach was used in combination with well established immunoassay experiments for the identification of a panel of urinary protein markers related to drug induced nephrotoxicity in rats. The initial generation of an expanded set of markers was accomplished using the label-free LC-MS discovery screen and ELISA based analysis of six nephrotoxicity biomarker proteins. Diagnostic performance of the expanded analyte set was statistically compared to conventional nephrotoxicity biomarkers. False discovery rate (FDR) analysis revealed 18 and 28 proteins from the CDDP and DOX groups, respectively, exhibiting significant differences between the vehicle and treated groups. Multiplex SRM assays were constructed to more precisely quantify candidate markers selected from the discovery screen and immunoassay experiments. To evaluate the sensitivity and specificity for each of the candidate biomarkers, histopathology severity scores were used as a benchmark for renal injury followed by receiver-operating characteristic (ROC) curve analysis on selected biomarkers. Further examination of the best performing analytes revealed relevant biological significance after consideration of anatomical localization and functional roles. In summary, the inclusion of mass spectrometry together with conventional ELISA based assays resulted in the identification of an expanded set of biomarkers with a realistic potential for providing additional beneficial information in mechanistic investigations of drug induced kidney injury and with similar responsiveness to conventionally applied indicators of renal injury.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Chen L,Smith J,Mikl J,Fryer R,Pack F,Williams BJ,Phillips JA,Papov VV Jrdoi
10.1021/acs.chemrestox.7b00159subject
Has Abstractpub_date
2017-10-16 00:00:00pages
1823-1834issue
10eissn
0893-228Xissn
1520-5010journal_volume
30pub_type
杂志文章abstract：:Caffeine on alkaline hydrolysis produces caffeidine [1-methyl-4-(methylamino)-5-(N-methylcarbamoyl)imidazole] and caffeidine acid [N-[4-(5-carboxy-1-methylimidazolyl)]-N,N'-dimethylurea]. We now report the synthesis and chemical characterization of mononitrosocaffeidine [1-methyl-4-(N-methyl-N-nitrosoamino)-5-(N-methy...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00031a008
更新日期：1993-01-01 00:00:00
abstract：:The effect of adduct stereochemistry on the susceptibility to hydrolysis by snake venom (VPD) and bovine spleen (SPD) phosphodiesterases was investigated with short deoxyoligonucleotides containing defined adducts derived from alkylation of the exocyclic 6-amino group of dA by polycyclic aromatic hydrocarbon diol epox...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx010092l
更新日期：2001-09-01 00:00:00
abstract：:alpha-Methyldopamine (alpha-MeDA) is a metabolite of the serotonergic neurotoxicants 3,4-(+/-)-(methylenedioxy)amphetamine (MDA) and 3,4-(+/-)-(methylenedioxy)methamphetamine (MDMA). alpha-MeDA readily oxidizes, and in the presence of glutathione (GSH) it forms 5-(glutathion-S-yl)-alpha-methyldopamine [5-(glutathion-S...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx9501546
更新日期：1996-03-01 00:00:00
abstract：:The reaction of chromium(VI) with hydrogen peroxide was studied in the presence of glutathione. In vitro, reaction of chromium(VI) with hydrogen peroxide alone led to production of hydroxyl radical as the significant reactive intermediate, while reaction of chromium(VI) with glutathione led to formation of two chromiu...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00018a016
更新日期：1990-11-01 00:00:00
abstract：:Two samples of highly pure multiwalled carbon nanotubes (MWCNTs) similar in hydrophobicity and surface reactivity were prepared with similar length, <5 μm, but markedly different diameter (9.4 vs 70 nm). The samples were compared for their cytotoxic activity, uptake, and ability to induce oxidative stress (ROS product...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx200255h
更新日期：2012-01-13 00:00:00
abstract：:The reactions of calf thymus DNA with four 1,3-dialkyl-3-acyltriazenes were studied alone or in the presence of pig liver esterase in pH 7.4 phosphate buffer for varying lengths of time. The best alkylating agent in the absence of esterase was determined to be 1,3-dimethyl-3-carbethoxytriazene (DMC), followed in order...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00028a013
更新日期：1992-07-01 00:00:00
abstract：:2,5-Hexanedione (2,5-HD) is the neurotoxic gamma-diketone metabolite of the industrial solvent n-hexane. Substantial evidence indicates that 2,5-HD reacts with neurofilament protein lysine epsilon-amines to yield 2,5-dimethylpyrrole adducts and that this reaction is critical to the mechanism of toxicity. Alkylpyrroles...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00040a011
更新日期：1994-07-01 00:00:00
abstract：:The cytotoxic activity of N-methyl-N-nitrosourea (MNU), streptozotocin, and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was determined in cell culture by using a P388 cell growth rate inhibition assay. These agents appear to have very different activities when inhibition is related to the agent concentration in the cu...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00009a006
更新日期：1989-05-01 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：:2'-Deoxyoxanosine (dOxo) is a novel DNA lesion produced from dGuo by reaction with nitrous acid or nitric oxide [Suzuki, T., Yamaoka, R., Nishi, M., Ide, H., and Makino, K. (1996) J. Am. Chem. Soc. 118, 2515-2516]. We investigated the reaction of dOxo with glycine (Gly) under physiological conditions. When 5 mM dOxo w...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx990164x
更新日期：2000-04-01 00:00:00
abstract：:Capillary liquid chromatography/microelectrospray mass spectrometry has been applied to the detection of deoxyribonucleoside adducts of the food-derived mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) from in vitro and in vivo sources. Constant neutral loss (CNL) and selective reaction monitoring (SRM) techniques...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx990060m
更新日期：1999-10-01 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx200259y
更新日期：2011-10-17 00:00:00
abstract：:2-(Glutathion-S-yl)-1,4-benzoquinone was found to be remarkably unstable in phosphate buffer (pH 7.4) even in the absence of oxygen. Intramolecular addition of the alpha-amino group of the glutamate residue to the quinone ring yielded ultimately 2,3-(glutathion-N, S-yl)-1,4-benzoquinone and 2,6-(glutathion-N,S-yl)-1,4...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx9800699
更新日期：1998-10-01 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.6b00290
更新日期：2017-02-20 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
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00025a023
更新日期：1992-01-01 00:00:00
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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：:The deamination of DNA bases by three alpha-nitrosaminoaldehydes, butylethanalnitrosamine, methylethanalnitrosamine, and N-nitroso-2-hydroxymorpholine (NHMOR), the direct metabolite of potent animal carcinogen N-nitrosodiethanolamine, was demonstrated by a set of in vitro experiments. The deamination of guanine, adeni...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx990126d
更新日期：2000-02-01 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx050095o
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx025558u
更新日期：2002-09-01 00:00:00
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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：:Sulfamethoxazole (SMX) is an important antibiotic in the management of patients with cystic fibrosis, but allergic reactions may develop thus restricting therapy. The aim of this study was to utilize drug (metabolite) antigens to diagnose SMX-mediated allergic reactions in patients with cystic fibrosis. Lymphocytes fr...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx100151v
更新日期：2010-06-21 00:00:00
abstract：:Cyadox is a novel derivative of quinoxaline-1,4-dioxides (QdNOs) with the potential to be developed as a feed additive. However, the pharmacological and toxicological bioactive molecules of cyadox and the molecular mechanism of its pharmacological and toxic actions remain unclear. In the present study, cyadox and its ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.8b00194
更新日期：2018-11-19 00:00:00
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
更新日期：2005-02-01 00:00:00
abstract：:The wide pH range reported for electronic cigarette (ECIG) liquids indicates that nicotine may be present in one or more chemical forms. The nicotine form affects the bioavailability and delivery of nicotine from inhaled products. Protonated nicotine is normally associated with counteranions in tobacco products. The c...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.7b00090
更新日期：2017-08-21 00:00:00
abstract：:alpha-Sulfate trans-tamoxifen and alpha-sulfate cis-tamoxifen were synthesized as proposed active metabolites of tamoxifen that react with DNA. alpha-Acetoxytamoxifen was prepared as a model-activated form to produce a reactive carbocation. Calf thymus DNA was reacted with alpha-hydroxytamoxifen or the activated forms...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx960114h
更新日期：1997-02-01 00:00:00
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00014a008
更新日期：1990-03-01 00:00:00
abstract：:The ability of the carcinogenic mycotoxin ochratoxin A (OTA) to react with reduced glutathione (GSH) has been assessed using electrospray ionization (ES)-MS techniques. On the basis of the assumption that OTA undergoes biotransformation into the reactive quinone species OTQ (6), a synthetic sample of the reduced form ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx0255929
更新日期：2002-12-01 00:00:00
abstract：:The diarrhetic shellfish toxin composition in the digestive glands of mussels collected in June 2001 from the Northern Adriatic sea was investigated by high-performance liquid chromatography coupled with electrospray ion trap mass spectrometry. Along with known yessotoxins (1, 3-6), identified by comparison of their r...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx025527z
更新日期：2002-07-01 00:00:00
abstract：:The crystal structure of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) has been determined by single-crystal X-ray crystallography. Crystals grown by evaporation of an aqueous solution form in the monoclinic space group P2(1)/n with two molecules of PhIP per asymmetric unit, along with six w...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx950168b
更新日期：1996-04-01 00:00:00
