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• W1512987462 abstract "Xenobiotics are chemical compounds introduced to living organisms that originate outside the body. A well-studied xenobiotic is benzo[a]pyrene (BP) a polyaromatic hydrocarbon (PAH) primarily introduced into the body via cigarette smoke as well as through environmental pollution. Once inside the body BP is ultimately metabolized into electrophilic benzo[a]pyrene- 78-diol-910-epoxide (BPDE) that reacts with and damages nucleophilic biomaterial including DNA. BPDE predominately targets specific genomic guanines at sites termed hotspots. BPDE hotspot damage can result in DNA mutations that alter key amino acids in proteins that are involved in cellular regulation eventually leading to cancer. This process occurs regularly in vivo within the TP53 gene at selected codons. TP53 codes for the p53 protein which is involved in cellular apoptosis. BPDE stereochemistry and cytosine methylation within hotspot codons are also important parameters that affect the eventual mutagenesis stemming from BPDE-guanine adducts.  Traditional detection of site-specific DNA damage can be expensive and time consuming. Electrochemical approaches can remedy these drawbacks. An electrochemical sensor was developed to detect DNA damage from (±)-anti-BPDE. A double stranded DNA (dsDNA) oligomer corresponding to a known hotspot sequence in the TP53 gene was immobilized on a gold electrode and then exposed to BPDE. Voltammetric measurements were then performed in the presence of electroactive C[subscript]12H[subscript]25V[superscript]2+C[subscript]6H[subscript]12V[superscript]2+C[subscript]12H[subscript]25 (V[superscript]2+ =44'-bipyridyl or viologen C[subscript]12Viologen). BPDE exposure causes DNA structural changes through the formation of bulky adducts that influence the C[subscript]12Viologen-DNA interaction. These structural changes affect the resulting C[subscript]12Viologen voltammetry. At wild type TP53 sequences BPDE exposure resulted in the emergence of a positive shifted C[subscript]12Viologen redox wave at -0.37 V. At an identical sequence containing 5-methylated cytosine at the hotspot location two waves emerged at -0.37 V and -0.54 V. These redox signals were muted when DNA was exposed to alternate xenobiotics or alternate sequences were exposed to BPDE. Overall this demonstrates sequence specific detection of DNA damage at this hotspot sequence. Differences in the voltammetric response suggest that the sensor is sensitive to the adduct stereochemistry. Additional studies were performed to monitor the effects of BP activation. Activation includes chemical oxidation of BP through association with reactive oxygen species or metabolism. Initial studies focused on the reaction of BP with DNA in the presence of hydrogen peroxide. DNA exposed to this reaction cocktail provided C[subscript]12Viologen voltammetry that was similar to that caused by BPDE exposure highlighted by a large SWV current increase at -0.37 V. Results were consistent with Fenton chemistry occurring in the damage buffer producing hydroxyl radicals from hydrogen peroxide and iron impurities. The hydroxyl radicals appear to activate BP producing a reactive species that results in BP-DNA adducts. Overall the data show a sequence-specific DNA hybridized sensor has the capability of providing hotspot and stereospecific genotoxicity information for benzo[a]pyrene derivatives." @default.
• W1512987462 created "2016-06-24" @default.
• W1512987462 creator A5088699272 @default.
• W1512987462 date "2011-01-01" @default.
• W1512987462 modified "2023-09-27" @default.
• W1512987462 title "ELECTROCHEMICAL DETECTION OF BENZO[A]PYRENE METABOLITE DNA DAMAGE : IMPLICATIONS OF NUCLEOBASE SEQUENCE AND ADDUCT STEREOCHEMISTRY" @default.
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