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

Yinzhi Zhao, Paul Toselli and Wande Li
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Yinzhi Zhao: Department of Biochemistry, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA
Paul Toselli: Department of Biochemistry, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA
Wande Li: Department of Biochemistry, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA

IJERPH, 2012, vol. 9, issue 2, 1-22

Abstract: To understand mechanisms for arsenic toxicity in the lung, we examined effects of sodium m -arsenite (As 3+ ) 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). As 3+ 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 ?I-tubulin in dosed lung cells and tissues. Spindle MT injuries by As 3+ were concomitant with chromosomal disorientations. As 3+ reduced the binding to tubulin of [ 3 H]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 As 3+ action upon tubulin through -SH groups. In response to As 3+ , cells elevated cellular thiols such as metallothionein. Taxol, a tubulin polymerization agent, antagonized both As 3+ and NEM induced MT depolymerization. MT–associated proteins (MAPs) essential for the MT stability were markedly suppressed in As 3+ -treated cells. Thus, tubulin sulfhydryls and MAPs are major molecular targets for As 3+ damage to the lung triggering MT disassembly cascades.

Keywords: trivalent arsenic (As 3+ ); microtubules (MTs); tubulin; tubulin mRNA; tubulin sulfhydryl groups (-SH); microtubule-associated proteins (MAPs); chromosomal disorientations; metallothionein; taxol (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2012
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