학술논문
Uncovering the Role of Methylmercury on DNA Lesions at Cytotoxic Concentrations in Glutathione-Depleted Cells: Insights from Experimental and Computational Studies.
Document Type
Academic Journal
Author
Das R; Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, Dadri, UP 201314, India.; Karri R; Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, Dadri, UP 201314, India.; Ruhvenile Biomedical OPC Pvt. Ltd., New Delhi 110070, Delhi, India.; Chalana A; Centre for Development of Biomaterials, Department of Chemistry & Biochemistry, Sharda University, Greater Noida, UP 201306, India.; Rai RK; Department of Chemistry, Indian Institute of Technology Tirupati, Tirupati, AP 517619, India.; Roy G; Department of Chemistry, Indian Institute of Technology Tirupati, Tirupati, AP 517619, India.
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 0366543 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-510X (Electronic) Linking ISSN: 00201669 NLM ISO Abbreviation: Inorg Chem Subsets: MEDLINE
Subject
Language
English
Abstract
Organomercurials (RHg + ), especially methylmercury (MeHg + ) and ethylmercury (EtHg + ), are considered to be more neurotoxic than the inorganic counterpart (Hg 2+ ). They cause massive DNA damage in cells, especially in neurons, where cellular glutathione (GSH) levels are significantly low. However, the mechanism by which RHg + exerts massive DNA damage at cytotoxic concentrations in brain cells remains obscure. In this study, we investigated the effect of RHg + on the structural and electronic properties of nucleosides and its effects on DNA damage. The direct interaction of RHg + with the nucleoside significantly weakens N -glycosidic bonds, decreases the C-H bond energy of sugar moieties, and increases the electrophilicity of the C 8 -center of purine bases. As a consequence, RHg + -conjugated DNA molecules are extremely labile and highly sensitive to any nucleophiles/radicals present in GSH-depleted cells and, thus, undergo enhanced oxidative and unusual alkylative DNA damage. We also report a functional model of organomercurial lyase, which showed excellent cytoprotective effect against RHg + -induced cytotoxicity; this reverses the activity of glutathione reductase inhibited by MeHgCl and ceases oxidative and alkylating DNA damage. This intriguing finding provides new mechanistic insight into the mode of action of organomercurials in GSH-depleted cells and their adverse effects on individuals with neurodegenerative disorders associated with oxidative stress.