Mechanism of asbestos-mediated DNA damage: role of heme and heme proteins.
Several observations, including studies from this laboratory, demonstrate that asbestos generates free radicals in the biological system that may play a role in the manifestation of asbestos-related cytotoxicity and carcinogenicity. It has also been demonstrated that iron associated with asbestos plays an important role in the asbestos-mediated generation of reactive oxygen species. Exposure to asbestos leads to degradation of heme proteins such as cytochrome P450-releasing heme in cytosol. Our simulation experiments in the presence of heme show that such 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 participation of iron, heme, and heme moiety of prostaglandin H synthetase in free radical generation from peroxides and hydroperoxides.
Rahman
Q
Q
Industrial Toxicology Research Centre, Lucknow, India. intox@itrc.simetd.emet.in
Mahmood
N
N
Khan
S G
SG
Arif
J M
JM
Athar
M
M
D000818:Animals; D017638:Asbestos, Crocidolite / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002417:Cattle; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004391:Dust / Q000009:adverse effects; D006418:Heme / Q000633:toxicity*; D006420:Hemeproteins / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000648:ultrastructure; D008861:Microsomes / Q000187:drug effects; D010084:Oxidation-Reduction; D051381:Rats; D017382:Reactive Oxygen Species / Q000502:physiology; D015719:Single-Strand Specific DNA and RNA Endonucleases / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D002273:Carcinogens; D004391:Dust; D006420:Hemeproteins; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D017638:Asbestos, Crocidolite; D006418:Heme; D004247:DNA; D015719:Single-Strand Specific DNA and RNA Endonucleases