The cytoskeleton as a target in quinone toxicity

Abstract

The exposure of mammalian cells to toxic concentrations of redox cycling and alkylating quinones causes marked changes in cell surface structure known as plasma membrane blebbing. These alterations are associated with the redistribution of plasma membrane proteins and the disruption of the normal organization of the cytoskeletal microfilaments which appears to be due mainly to actin cross-linking and dissociation of alpha-actinin from the actin network. The major biochemical mechanisms responsible for these effects seem to involve the depletion of cytoskeletal protein sulfhydryl groups and the increase in cytosolic Ca2+ concentration following the alkylation/oxidation of free sulfhydryl groups in several Ca2+ transport systems. Depletion of intracellular ATP is also associated with quinone-induced plasma membrane blebbing. However, ATP depletion occurs well after the onset of the morphological changes, and thus it does not seem to be causatively related to their appearance. Thiol reductants, such as dithiothreitol, efficiently prevent the oxidation of cytoskeletal protein thiols, the increase in cytosolic free Ca2+ concentration and cell blebbing induced by redox cycling, but not alkylating, quinones. These results demonstrate that alkylating and redox cycling quinones cause similar structural and biochemical modifications of the cytoskeleton by means of different mechanisms, namely alkylation and oxidation of critical sulfhydryl groups.