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

International Journal of Environmental Research and Public Health

Yinzhi Zhao¹  Paul Toselli¹ 

[1] Department of Biochemistry, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA;

关键词: trivalent arsenic (As³⁺);    microtubules (MTs);    tubulin;    tubulin mRNA;    tubulinsulfhydryl groups (-SH);    microtubule-associated proteins (MAPs);    chromosomal disorientations;    metallothionein;    taxol;   

DOI  :  10.3390/ijerph9020474

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.