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
[...] Read more.
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 βI-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 [
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 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.
Full article
