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標題: Effects of naphthalene quinonoids on the induction of oxidative DNA damage and cytotoxicity in calf thymus DNA and in human cultured cells
作者: Lin, P.H.
Pan, W.C.
Kang, Y.W.
Chen, Y.L.
Lin, C.H.
Lee, M.C.
Chou, Y.H.
Nakamura, J.
關鍵字: ras oncogene mutations;aldehydic dna;apurinic/apyrimidinic sites;dihydrodiol dehydrogenase;albumin adducts;breast-cancer;lesions;1,4-naphthoquinone;activation;stress
Project: Chemical Research in Toxicology
期刊/報告no:: Chemical Research in Toxicology, Volume 18, Issue 8, Page(s) 1262-1270.
The purpose of this study was to examine the differences in the induction of DNA damage and cytotoxic effects by quinonoid derivatives of naphthalene in calf thymus DNA (ct-DNA) and in human T47D breast cancer cells. Results indicated that copper(II) and NADPH were essential for causing oxidant-mediated aldehydic DNA lesions (ADLs), including abasic sites and aldehydic base/sugar lesions, in ct-DNA exposed to 1,2-naphthalenediol (NCAT), 1, naphthalenediol (NHQ), 1,2-naphthoquinone (1,2-NQ), and 1,4-naphthoquinone (1,4-NQ). The ADLs induced by naphthalene quinonoids in ct-DNA decrease in the rank order NCAT similar or equal to 1,2-NQ > NHQ >> 1,4-NQ. Results from the analyses in cells indicated that after 1.5-5 h of exposure all naphthalene quinonoids induced a cytotoxic response in T47D cells at concentrations 10-100,mu M or above, where NHQ and 1,4-NQ were similar to 5-10 times more efficient than NCAT and 1,2-NQ in the induction of cell death. In addition, NHQ, 1,2-NQ, and 1,4-NQ were not able to produce measurable levels of ADLs in cells at concentrations up to 1.25 mM, whereas NCAT (0.75-1.25 mM) induced a significant increase in the number of ADLs in T47D cells after 1.5 h of exposure when compared to control. The specific type of ADLs induced by NCAT is resistant to cellular excision repair pathway. Results from the measurements of reactive oxygen species (ROS) indicated that all naphthalene quinonoids induced increases in ROS formation in T47D cells. The induction of ROS formation in cells by naphthalene quinonoids decreases in the rank order 1,4-NQ similar or equal to 1,2-NQ > NHQ > NCAT. Overall, results from our investigation suggest that naphthalene quinonoids cause cell death at concentrations well below the concentrations at which they induce the formation of ADLs, perhaps by altering intracellular redox status.
ISSN: 0893-228X
DOI: 10.1021/tx050018t
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