Mechanism of asbestos-mediated DNA damage: role of heme and heme proteins

Our plain-English summary of Mechanism of asbestos-mediated DNA damage: role of heme and heme proteins, by Q. Rahman, N. Mahmood, S.G. Khan, et al (Environmental Health Perspectives, 1997).

The study

• Authors: Q. Rahman, N. Mahmood, S.G. Khan, J.M. Arif, M. Athar
• Journal: Environmental Health Perspectives
• Published: 1997;105 Suppl 5(Suppl 5):1109-12
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This was a laboratory study by Rahman and colleagues. It tested, in test tubes, whether heme and heme-containing proteins add to the DNA damage caused by asbestos. No people or live animals were exposed. Calf thymus DNA was incubated with crocidolite asbestos and several peroxides, with or without horseradish peroxidase (HRP). HRP is a heme-containing enzyme that the authors described as similar to prostaglandin H synthetase. In other tests, the DNA was incubated with breakdown products of rat lung microsomes that had been treated with crocidolite. Damage was measured as the percent of DNA broken down by an enzyme. With hydrogen peroxide, 40.54% of crocidolite-treated DNA was broken down. Adding HRP raised this to 54.73% (100 units) and 67.34% (200 units). Breakdown products of crocidolite-treated microsomes with hydrogen peroxide gave 86.06%, compared with 6.12% for untreated microsomes. An iron-binding drug, desferal, only partly reduced the damage (data not shown). The authors concluded that asbestos may cause DNA damage by generating reactive oxygen species through iron-, heme- and/or prostaglandin H synthetase-driven breakdown of peroxides.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (cell-free, in vitro) experiment
• Who was studied: No human or animal subjects. The experiments used purified calf thymus DNA, plus lung microsomes (cell fractions) taken from rats. Each condition was run 6 times (n=6).
• Exposure: The dust samples listed were UICC chrysotile and crocidolite reference asbestos and Indian chrysotile (30 pm particle size as printed). The reported experiments used crocidolite (1 mg/ml) together with heme, horseradish peroxidase (100 to 200 units), or breakdown products of rat lung microsomes. These were combined with hydrogen peroxide, benzoyl peroxide, cumene hydroperoxide, tertiary-butyl hydroperoxide or ABIN at 40 mM.
• Main results:
  • HRP increased the breakdown of crocidolite-treated DNA. With hydrogen peroxide (the peroxide giving the most damage), DNA hydrolyzed was 40.54±2.10% with crocidolite alone, 54.73±2.18% with 100 U HRP and 67.34±3.20% with 200 U HRP (mean±SE, n=6; p less than 0.001 compared with DNA alone or DNA plus crocidolite alone). Hydrogen peroxide with DNA but no crocidolite gave 3.10±0.16%.
  • Damage to the deoxyribose sugar of DNA (thiobarbituric acid-reactive products) was 3.42±0.27 nmol with crocidolite plus hydrogen peroxide. Adding HRP raised this to 5.34±0.36 nmol (p less than 0.05). All other combinations in that table were 0.00, and the other peroxides did not produce sugar damage.
  • Breakdown products of crocidolite-treated rat lung microsomes with hydrogen peroxide gave 86.06±6.02% DNA hydrolyzed (p less than 0.001). The comparison values were 6.12±0.34% with untreated microsomes and 6.00±0.39% with DNA alone.
  • With crocidolite-treated microsome products, only hydrogen peroxide (1.92±0.09) and ABIN (1.08±0.07) produced damage to the DNA sugar moiety. All other conditions were 0.00.
  • Desferal, an iron chelator, only partially suppressed DNA damage (data not shown). The authors took this to mean that iron leached from asbestos is only partly responsible for the damage.
  • The authors reported that heme-catalyzed DNA damage was similar to HRP-catalyzed damage but much smaller in magnitude. Data for heme alone were not shown.
• The authors' conclusion: The authors concluded that asbestos may cause DNA damage by generating reactive oxygen species through iron-, heme- and/or prostaglandin H synthetase-catalyzed decomposition of peroxides and hydroperoxides. They also concluded that asbestos may act through a different mechanism from carcinogens that bind to or alkylate DNA.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Crocidolite.

Medical terms in this study, explained in our Lexicon: Reactive Oxygen Species (ROS).

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