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Microtubules as a Critical Target for Arsenic Toxicity in Lung Cells in Vitro and in Vivo

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Author(s): Yinzhi Zhao | Paul Toselli | Wande Li

Journal: International Journal of Environmental Research and Public Health
ISSN 1660-4601

Volume: 9;
Issue: 2;
Start page: 474;
Date: 2012;
Original page

Keywords: trivalent arsenic (As3+) | microtubules (MTs) | tubulin | tubulin mRNA | tubulin sulfhydryl groups (-SH) | microtubule-associated proteins (MAPs) | chromosomal disorientations | metallothionein | taxol

ABSTRACT
To understand mechanisms for arsenic toxicity in the lung, we examined effects of sodium m-arsenite (As3+) on microtubule (MT) assembly in vitro (0–40 µM), in cultured rat lung fibroblasts (RFL6, 0–20 µM for 24 h) and in the rat animal model (intratracheal instillation of 2.02 mg As/kg body weight, once a week for 5 weeks). As3+ induced a dose-dependent disassembly of cellular MTs and enhancement of the free tubulin pool, initiating an autoregulation of tubulin synthesis manifest as inhibition of steady-state mRNA levels of bI-tubulin in dosed lung cells and tissues. Spindle MT injuries by As3+ were concomitant with chromosomal disorientations. As3+ reduced the binding to tubulin of [3H]N-ethylmaleimide (NEM), an -SH group reagent, resulting in inhibition of MT polymerization in vitro with bovine brain tubulins which was abolished by addition of dithiothreitol (DTT) suggesting As3+ action upon tubulin through -SH groups. In response to As3+, cells elevated cellular thiols such as metallothionein. Taxol, a tubulin polymerization agent, antagonized both As3+ and NEM induced MT depolymerization. MT–associated proteins (MAPs) essential for the MT stability were markedly suppressed in As3+-treated cells. Thus, tubulin sulfhydryls and MAPs are major molecular targets for As3+ damage to the lung triggering MT disassembly cascades.
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