Effect of Free Radical on DNA

Effect of Free Radical on DNA

dr I Gusti Kamasan Nyoman Arijana, S.Ked, M.Si.Med

                                                                                                                                            Departement of Histologi, Faculty of Medicine, Udayana University

Metabolic diseases such as obesity, type 2 diabetes mellitus, and atherosclerosis are increasingly occurring throughout the world. Patients with the disease have high levels of fatty acids and sugars resulting in an increase in acetyl CoA production. As a result there is a large burden (excessive superoxide) on the electron chain in the mitochondria. Subsequently there is an over-conversion of superoxide to excessive hydrogen peroxide and ultimately oxidative stress can occur if natural antioxidants are not available in sufficient quantities. Oxidative stress occurs when free radicals such as superoxides, hydrogen peroxide, etc. have exceeded the amount of antioxidants available. These free radicals react with proteins, fats and nucleic acids such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in the body's cells and have a particularly damaging effect on DNA.^1,2

As well-known DNA chains have thymine bases, cytosine, guanine, adenine. If the thymine base is exposed to hydrogen peroxide, 5,6-dihydro-5,6-dihydroxythymine (thymine glycol) will be formed and this will significantly disrupt the DNA duplex structure to be extrahelix. This structure according to research will be lethal to cells. Besides thymine glycol, it can also form dihydrothymine, which does not inhibit the enzyme DNA polymerase, so it is neither lethal nor mutagenic. If the cytosine base is exposed to hydrogen peroxide, cytosine glycol is formed which is very unstable and easily deaminated into uracil glycol or can also become dehydrated to 5-hydroxycytosine (5-OHC). On the other hand uracil glycol can also be dehydrated to 5-hydroxyuracil (5-OHU). Uracil glycol and 5-OHU have the potential for potential premutagenic lesions. However, 5-OHC is less cytotoxic and lacks mutagenic properties. If guanine bases are exposed to hydrogen peroxide, 7,8-dihydro-8-oxoguanine (8-oxoG) and 8-oxoG are generally biomarkers of oxidative stress on DNA. 8-oxoG lesions are not lethal but mutagenic. If the adenine base is exposed to hydrogen peroxide, 7,8-dihydro-8-oxoadenine (8-oxoA) is formed where the lesion does not interfere with DNA polymerase. In addition, 8-oxoA lesions are not mutagenic or cytotoxic. However, if 4,6-Diamino-5-formamidopyrimidine (Fapy-A) is formed, this lesion is able to block DNA polymerase and has a lethal potential. ^1,2

As is well known cells also have the ability to produce antioxidants in addition to getting antioxidants from outside the body. However, if a lesion in DNA has occurred due to oxidative stress, the cell still has the ability to repair it, but this is outside the scope of this paper. Therefore it is very important to realize the need for antioxidants from outside the body if the cells are not able to meet the production of natural antioxidants so that the body's cells do not experience damage which will eventually cause disease in human organs.

References

1. Wallace SS. Biological consequences of free radical-damaged DNA bases1, 2 1Guest Editor: Miral Dizdaroglu 2This article is part of a series of reviews on “Oxidative DNA Damage and Repair.” The full list of papers may be found on the homepage of the journal. Free Radical Biology and Medicine. 2002/07/01/ 2002;33(1):1-14.

2. Dizdaroglu M, Jaruga P. Mechanisms of free radical-induced damage to DNA. Free Radic Res. 2012;46(4):382-419.