Elucidating Organ-Specific Metabolic Toxicity Chemistry from Electrochemiluminescent Enzyme/DNA Arrays and Bioreactor Bead-LC-MS/MS

Chemical Science
Dhanuka P WasalathanthriJames F Rusling

Abstract

Human toxic responses are very often related to metabolism. Liver metabolism is traditionally studied, but other organs also convert chemicals and drugs to reactive metabolites leading to toxicity. When DNA damage is found, the effects are termed genotoxic. Here we describe a comprehensive new approach to evaluate chemical genotoxicity pathways from metabolites formed in-situ by a broad spectrum of liver, lung, kidney and intestinal enzymes. DNA damage rates are measured with a microfluidic array featuring a 64-nanowell chip to facilitate fabrication of films of DNA, electrochemiluminescent (ECL) detection polymer [Ru(bpy)2(PVP)10](2+) {(PVP = poly(4-vinylpyridine)} and metabolic enzymes. First, multiple enzyme reactions are run on test compounds using the array, then ECL light related to the resulting DNA damage is measured. A companion method next facilitates reaction of target compounds with DNA/enzyme-coated magnetic beads in 96 well plates, after which DNA is hydrolyzed and nucleobase-metabolite adducts are detected by LC-MS/MS. The same organ enzymes are used as in the arrays. Outcomes revealed nucleobase adducts from DNA damage, enzymes responsible for reactive metabolites (e.g. cyt P450s), influence of bioconjugation, r...Continue Reading

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Citations

Apr 5, 2016·Analytical Chemistry·James F Rusling, Eli G Hvastkovs
Jun 24, 2015·Chemical Communications : Chem Comm·Rajasekhara Nerimetla, Sadagopan Krishnan
Jun 9, 2017·Electroanalysis·Kiran Bano, James F Rusling
Sep 22, 2020·Molecular Pharmaceutics·Abdul BasitBhagwat Prasad
Dec 14, 2016·Analytical Chemistry·Lingling LiJun-Jie Zhu

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Methods Mentioned

BETA
chip
quartz crystal microbalance
chips
electrophoresis

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