Humans are constantly exposed to a wide range of reactive and toxic chemicals from the different sources in everyday life. Identification of the exposed chemical helps in the detection and understanding the exposure associated adverse health effects. Covalent adducts of proteins and DNA formed after xenobiotics exposure may serve as readily measurable indicators of these exposures. Measuring the exposed chemicals with focus on adducts resulting from the nucleophilic interactions with blood proteins is useful in the development of diagnostic markers. Particularly, the most abundant proteins such as albumin and hemoglobin acts as dominant scavengers for many reactive chemicals in blood and can serve as excellent diagnostic candidates to determine the type of chemical exposure. This review focuses on the potential application of an adductomics approach for the screening of bimolecular adducts of chemical warfare agents (CWAs). Recent incidents of CWAs use in Syria, Malaysia, and the UK illustrate the continuing threat of chemical warfare agents in the modern world. Detection of CWAs and their metabolites in blood or in other body fluids of victims depends on immediate access to victims. Concentrations of intact CWAs in body fluids of surviving victims may decline rapidly within a few days. Certain CWAs, particularly nerve agents and vesicants, form covalent bonds with certain amino acids to form CWA-protein adducts. Proteins that are abundant in the blood, including albumin and hemoglobin, may carry these adducts longer after the original exposure. We searched MEDLINE and ISI Web of Science databases using the key terms "adductomics" "adducts of CWAs," "CWAs adducts detection in the biological samples," "protein adducts of CWAs," alone and in combination with the keywords "detection" "intoxication" "exposure" "adverse effects" and "toxicity." We also included non-peer-reviewed sources such as text books, relevant newspaper reports, and applicable Internet resources. We screened bibliographies of identified articles for additional relevant studies including non-indexed reports. These searches produced 1931 citations of which only relevant and nonduplicate citations were considered for this review. The analysis of biomedical samples has several purposes including detecting and identifying the type of chemical agent exposed, understanding the biological mechanism, assists in giving adequate treatment, determining the cause of death and providing evidence in a court of justice for forensic investigations. Rapid advances in the mass spectrometry to acquire high-quality data with greater resolution enabled the analysis of protein and DNA adducts of xenobiotics including CWAs and place the rapidly advancing 'adductomics' next to the other "-omics" technologies. Adductomics can serve as a powerful bioanalytical tool for the verification of CWAs exposure. This review mostly describes the protein adducts for nerve agents and vesicants, outlines the procedures for measuring adducts, and suggests the evolving (or future) use of adducts in the detection and verification of CWAs.
Doxorubicin (DOX) adalah salah satu ubat kemoterapi yang paling berkesan untuk merawat pelbagai neoplasma seperti leukemia, limfoma dan kanser payudara. Walau bagaimanapun, ia sering dikaitkan dengan kardiomiopati. Pada masa ini, tiada rawatan yang sesuai untuk mengurangkan kesan kardiomiopati tanpa kesan sampingan yang ketara. Oleh itu, kajian ini bertujuan untuk mengkaji kesan-kesan perlindungan potensi ekstrak benih padi (RSE) terhadap kesitotoksikan yang disebabkan oleh DOX menggunakan kajian kultur sel vitro. Keupayaan antioksidan RSE dinilai, dan hasilnya menunjukkan jumlah kandungan fenolik yang lebih rendah (TPC), tetapi jumlah kandungan flavonoid total (TFC) dan kapasiti antioksidan yang setara trolox (TEAC), dibandingkan dengan ekstrak benih wheatgrass. Satu siri eksperimen spektroskopi penyerapan dan pendarfluor menunjukkan bahawa RSE boleh menghalang pembentukan kompleks DOX-DNA pada kepekatan yang diuji. Tambahan pula, daya maju sel kardiomiosit sel, H9c2 (2-1), telah diuji selepas 24, 48 dan 72 jam rawatan DOX terhadap RSE menggunakan ujian proliferasi sel berdasarkan garam tetrazolium (MTS reagent). Hasilnya menunjukkan kesan perlindungan yang signifikan terhadap RSE terhadap kesitotoksikan yang disebabkan oleh DOX. Jalur sel karsinoma nasofarinks, HK1, digunakan sebagai kawalan untuk menentukan sama ada keberkesanan DOX terjejas oleh pentadbiran bersama RSE. Hasilnya tidak menunjukkan kesan negatif terhadap keberkesanan dadah. Pelbagai sifat berfaedah RSE menunjukkan potensi kuatnya untuk membangunkan agen kardioprotektif untuk melengkapi rawatan DOX dalam tetapan klinikal.
Aristolochic acid I (AAI) is a well-known genotoxic kidney carcinogen. Metabolic conversion of AAI into the DNA-reactive aristolactam-nitrenium ion is involved in the mode of action of tumor formation. This study aims to predict in vivo AAI-DNA adduct formation in the kidney of rat, mouse and human by translating the in vitro concentration-response curves for AAI-DNA adduct formation to the in vivo situation using physiologically based kinetic (PBK) modeling-based reverse dosimetry. DNA adduct formation in kidney proximal tubular LLC-PK1 cells exposed to AAI was quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. Subsequently, the in vitro concentration-response curves were converted to predicted in vivo dose-response curves in rat, mouse and human kidney using PBK models. Results obtained revealed a dose-dependent increase in AAI-DNA adduct formation in the rat, mouse and human kidney and the predicted DNA adduct levels were generally within an order of magnitude compared with values reported in the literature. It is concluded that the combined in vitro PBK modeling approach provides a novel way to define in vivo dose-response curves for kidney DNA adduct formation in rat, mouse and human and contributes to the reduction, refinement and replacement of animal testing.
Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts' generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles' activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R(2)>0.7). Time-dependent appearance of γ-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs' hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs' activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines.
Matched MeSH terms: DNA Adducts/analysis*; DNA Adducts/metabolism
Polycyclic aromatic hydrocarbons (PAHs) are persistent pollutants and chemically a class of structurally similar chemical compounds characterized by the presence of fused aromatic rings. This research was undertaken to find out immunotoxic effects produced by pyrene, phenanthrene and fluoranthene. These chemicals were injected into developing chicks at three dose levels (0.2, 2 and 20 mg per kg) through allantioc route to rule out possible mechanisms involved in immunotoxicity. DNA adduct produced by PAHs in immune organs were analyzed by DNA adduct enzyme-linked immunosorbent assay (ELISA) kit and DNA damage was assessed by comet assay. A significant increase in the DNA adduct levels was found in thymus and bursa in 2 mg and 20 mg dose levels of pyrene, fluoranthene and phenanthrene treated groups, whereas those in spleen simulated the value of controls. Comet assay indicated that PAHs especially pyrene, fluoranthene and phenanthrene were capable of inducing increased level of comet parameters in thymus at all the dose levels. Bursa of Fabricius and spleen also showed a gradual rise in comet parameters corresponding to all dose levels, but the increase was more marked as in thymus. Thus, it can be concluded that DNA adducts produced by PAHs lead to single-strand breaks and reduced DNA repair, which ultimately begin a carcinogenic process. Hence, this experiment can be considered as a strong evidence of genotoxic potential of PAHs like pyrene, phenanthrene and fluoranthene in developing chicks.