MECHANISM OF ASBESTOS-MEDIATED DNA-DAMAGE - ROLE OF HEME AND HEME-PROTEINS

Several observations, including studies from this laboratory, demonstr ate that asbestos generates free radicals in the biological system tha t may play a role in the manifestation of asbestos-related cytotoxicit y and carcinogenicity. It has also been demonstrated that iron associa ted with asbestos plays an important role in the asbestos-mediated gen eration of reactive oxygen species. Exposure to asbestos leads to degr adation of heme proteins such as cytochrome P450-releasing heme in cyt osol. Our simulation experiments in the presence of heme snow that suc h asbestos-released heme may increase lipid peroxidation and can cause DNA damage, Further, heme and horseradish peroxidase (HRP) can cause extensive DNA damage in the presence of asbestos and hydrogen peroxide /organic peroxide/hydroperoxides. HRP catalyzes oxidation reactions in a manner similar to that of prostaglandin H synthetase. Iron released from asbestos is only partially responsible for DNA damage. However, our studies indicate that DNA damage mediated by asbestos in vivo may be caused by a combination of effects such as the release and particip ation of iron, heme, and heme moiety of prostaglandin H synthetase in free radical generation from peroxides and hydroperoxides.