Role of Iron in the Cellular Effects of Asbestos

Abstract

Research to understand how the physical characteristics of asbestos fibers impact the pathological effects has intensified in the past 10 years. The role that iron, intrinsic or acquired, may play has been the subject of many of these investigations. Asbestos catalyzes many of the same reactions that iron does, including lipid peroxidation and DNA damage. At physiological pH, mobilization of iron from the fibers by a low-molecular-weight chelator greatly enhances these reactions. Iron is also mobilized from asbestos fibers in human lung epithelial (A549) cells after the fibers are endocytized. The iron appears to move from a low-molecular-weight pool to nonferritin proteins and ferritin. The amount of iron in the low-molecular-weight pool was directly correlated with the toxicity of the asbestos. Glutathione (CSH) levels in these cells were dramatically reduced after asbestos treatment as a result of CSH efflux. This was not related to the iron associated with the fibers, but appeared to be due in some way to the silicate structure. The presence of the mobilized iron in the cells depleted of CSH creates a very oxidizing environment. Asbestos treatment of cells resulted in DNA oxidation, as assessed by formation of 8-hydroxy-2’-deoxyguanosine (8-oxo-dCJ. The DNA oxidation was dependent upon the iron associated with the fibers and the enzymatic generation of ^• NO by the cells. The induction of the inducible form of nitric oxide synthase (iNOS), responsible for the production of “NO, was dependent upon the presence of iron from the fibers and the decrease in CSH. One without the other did not lead to induction of iNOS. Asbestos was mutagenic in hgprt-gpt⁺ V79 Chinese hamster lung cells. The mutagenicity was dependent upon iron, intrinsic or acquired. Addition of ^• NO synergistically increased the mutagenicity of the asbestos, suggesting that in cells that respond to asbestos by making ^• NO, the response will be enhanced. This also suggests that the responses will be enhanced in the presence of activated macrophages producing ^• NO or in the presence of cigarette smoke, because of the presence of ^• NO and iron chelators in the smoke.