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Microtubules as a critical target for arsenic toxicity in lung cells in vitro and in vivo.

Authors
  • 1
Type
Published Article
Journal
International journal of environmental research and public health
1660-4601
Publication Date
Volume
9
Issue
2
Pages
474–495
Identifiers
DOI: 10.3390/ijerph9020474
PMID: 22470304
Source
Medline
Keywords
  • Chromosomal Disorientations
  • Metallothionein
  • Microtubule-Associated Proteins (Maps)
  • Microtubules (Mts)
  • Taxol
  • Trivalent Arsenic (As3+)
  • Tubulin
  • Tubulin Mrna
  • Tubulinsulfhydryl Groups (-Sh)

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 βI-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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