Screening Genotoxicity Chemistry with Microfluidic Electrochemiluminescent Arrays

This review describes progress in the development of electrochemiluminescent (ECL) arrays aimed at sensing DNA damage to identify genotoxic chemistry related to reactive metabolites. Genotoxicity refers to chemical or photochemical processes that damage DNA with toxic consequences. Our arrays feature DNA/enzyme films that form reactive metabolites of test chemicals that can subsequently react with DNA, thus enabling prediction of genotoxic chemical reactions. These high-throughput ECL arrays incorporating representative cohorts of human metabolic enzymes provide a platform for determining chemical toxicity profiles of new drug and environmental chemical candidates. The arrays can be designed to identify enzymes and enzyme cascades that produce the reactive metabolites. We also describe ECL arrays that detect oxidative DNA damage caused by metabolite-mediated reactive oxygen species. These approaches provide valuable high-throughput tools to complement modern toxicity bioassays and provide a more complete toxicity prediction for drug and chemical product development.

[1]  J. Schenkman,et al.  Metabolic toxicity screening using electrochemiluminescence arrays coupled with enzyme-DNA biocolloid reactors and liquid chromatography-mass spectrometry. , 2012, Annual review of analytical chemistry.

[2]  J. Labuda,et al.  Voltammetric detection of damage to DNA caused by nitro derivatives of fluorene using an electrochemical DNA biosensor , 2010, Analytical and bioanalytical chemistry.

[3]  J. Rusling.  Sensors for Genotoxicity and Oxidized DNA , 2005 .

[4]  J. Rusling,et al.  Electrochemiluminescent Array to Detect Oxidative Damage in ds-DNA Using [Os(bpy)2(phen-benz-COOH)]2+/Nafion/Graphene Films. , 2016, ACS sensors.

[5]  James F Rusling,et al.  State-of-the-Art Metabolic Toxicity Screening and Pathway Evaluation. , 2016, Analytical chemistry.

[6]  B. Aggarwal,et al.  Oxidative stress, inflammation, and cancer: how are they linked? , 2010, Free radical biology & medicine.

[7]  H. Yamazaki,et al.  Characterization of microsomal cytochrome P450 enzymes involved in the oxidation of xenobiotic chemicals in human fetal liver and adult lungs. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[8]  F. Guengerich,et al.  Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. , 2001, Chemical research in toxicology.

[9]  J. Rusling.  Sensors for toxicity of chemicals and oxidative stress based on electrochemical catalytic DNA oxidation. , 2004, Biosensors & bioelectronics.

[10]  J. Barek,et al.  Electrochemical DNA biosensor for detection of DNA damage induced by hydroxyl radicals. , 2017, Bioelectrochemistry.

[11]  J. Rusling,et al.  Simultaneous direct electrochemiluminescence and catalytic voltammetry detection of DNA in ultrathin films. , 2003, Journal of the American Chemical Society.

[12]  James F Rusling,et al.  High-throughput metabolic genotoxicity screening with a fluidic microwell chip and electrochemiluminescence. , 2013, Lab on a chip.

[13]  A. Collins,et al.  Oxidative stress in humans: validation of biomarkers of DNA damage. , 2002, Carcinogenesis.

[14]  Miroslav Fojta,et al.  Recent progress in electrochemical sensors and assays for DNA damage and repair , 2016 .

[15]  Z. Ďuračková.  Some current insights into oxidative stress. , 2010, Physiological research.

[16]  J. D. Stuart,et al.  Oscillating formation of 8-oxoguanine during DNA oxidation. , 2003, Journal of the American Chemical Society.

[17]  James F Rusling,et al.  Electrochemical catalysis with redox polymer and polyion-protein films. , 2003, Journal of colloid and interface science.

[18]  E. Paleček,et al.  Past, present and future of nucleic acids electrochemistry. , 2002, Talanta.

[19]  J. Schenkman,et al.  Electrochemiluminescent/voltammetric toxicity screening sensor using enzyme-generated DNA damage. , 2007, Biosensors & bioelectronics.

[20]  Dhanuka P Wasalathanthri,et al.  Thin multicomponent films for functional enzyme devices and bioreactor particles. , 2014, Soft matter.

[21]  J. A. Bond.  Review of the toxicology of styrene. , 1989, Critical reviews in toxicology.

[22]  M. Smyth,et al.  Direct electrochemiluminescence detection of oxidized DNA in ultrathin films containing [Os(bpy)2(PVP)10]2+. , 2004, Journal of the American Chemical Society.

[23]  Y. Monden,et al.  Identification and quantification of tamoxifen-DNA adducts in the liver of rats and mice. , 2001, Chemical research in toxicology.

[24]  Benveniste,et al.  Cytochrome P450 , 1993, Handbook of Experimental Pharmacology.

[25]  S. Krishnan,et al.  Thin film voltammetry of metabolic enzymes in rat liver microsomes. , 2007, Electrochemistry communications.

[26]  N. Tretyakova,et al.  Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers , 2002, Oncogene.

[27]  S. Krishnan,et al.  Human cyt P450 mediated metabolic toxicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) evaluated using electrochemiluminescent arrays. , 2009, Molecular bioSystems.

[28]  J. Schenkman,et al.  Biochemical applications of ultrathin films of enzymes, polyions and DNA. , 2008, Chemical communications.

[29]  J. Barek,et al.  Voltammetric Determination of 2‐Aminofluoren‐9‐one and Investigation of Its Interaction with DNA on a Glassy Carbon Electrode , 2015 .

[30]  B. Halliwell,et al.  Oxygen toxicity, oxygen radicals, transition metals and disease. , 1984, The Biochemical journal.

[31]  J. Schenkman,et al.  Screening for Reactive Metabolites Using Genotoxicity Arrays and Enzyme/DNA Biocolloids , 2010 .

[32]  M. Fojta.  Detecting DNA Damage with Electrodes , 2005 .

[33]  Xiaochao Ma.  Drug Metabolism Handbook: Concepts and Applications , 2009 .

[34]  Abraham Nyska,et al.  Invited Review: Oxidation of Biological Systems: Oxidative Stress Phenomena, Antioxidants, Redox Reactions, and Methods for Their Quantification , 2002, Toxicologic pathology.

[35]  J. Barek,et al.  Voltammetry at a Hanging Mercury Drop Electrode as a Tool for the Study of the Interaction of Double-stranded DNA with Genotoxic 4-Nitrobiphenyl , 2016 .

[36]  Dhanuka P Wasalathanthri,et al.  Efficient bioelectronic actuation of the natural catalytic pathway of human metabolic cytochrome P450s. , 2011, Journal of the American Chemical Society.

[37]  M. Gross,et al.  Binding of benzo[a]pyrene to DNA by cytochrome P-450 catalyzed one-electron oxidation in rat liver microsomes and nuclei. , 1990, Biochemistry.