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Role of Oxygen Free Radical in Cancer Promotion

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“From last decade our view over cancer is been changing, we are shifting to a new paradigm”, says Donald Malins of Pacific Northwest Research Foundation in Seatelle. Free radicals have become the major focus in regards to cancer. Despite the fact that oxygen is essential for daily living, it is also capable of participating in potentially toxic reactions involving oxygen free radicals and transition metals such as Fe that damages membranes, proteins and nucleic acid. Anti-oxidants generally protects oxidative damage and the reactions caused by oxygen free radicals, but in case of excess production of oxygen free radicals or weakened defense mechanism, oxidative damage occurs resulting in several pathological conditions including aging, carcinogenesis and stroke.(Ames BN, 1983, Cerutti P A. 1985).

In carcinogenesis process the DNA structure is totally changed due to alteration of nucleotide and the helical structure of the molecule. (Malins). This paper contributes considerable knowledge about the involvement of various free radicals in the process of oxidative stress, DNA damage, and tissue injury and thus leading to cancer. Carcinogenesis would be reviewed in brief with empirical data’s.

2. Oxygen Free Radicals: Oxygen molecules that have lost or gained an electron are called as free radicals. (Haliiiwell B, Gutteridge JMC). Usually Free radical contains electrons which are unpaired and are able to survive independently. Generally the orbit with single electron tries to atrack an unpaired electron from the other orbit. This gaining and loosing of electron are named as reduction and oxidation respectively. (Goodyear – Bruch C, Pierce JD).

Reduction and oxidation are common process occurring in human body involved in balancing chemical reactions. Often human body tires to maintain a balance between the production of oxygen free radicals and the amount of antioxidants, thus preventing the body from cellular damage. (Droge W, 2002). Increase in production of oxidants or antioxidants alter the chemical balance resulting in oxidative stress and damages cell proteins and DNA by chemically altering them. (Kohen R, Nyska A, 2002).

Free radicals which are highly reactive often involves in chain reactions with other less reactive molecule causing cellular damage. Hydrogen peroxide, superoxide, hydroxyl radical, nitric oxide (NO•) and nitrogen dioxide (NO2•) are few examples of free radicals. When cell grows they take in oxygen and release free radicals, this is a common process in human body. Various researches have proved the involvement of free radicals in degenerative diseases such as cancer and aging.

3. Role of Free Radicals in Oxidative Stress: Oxidative stress occurs when there is an excess production of free radicals like reactive oxygen species in the cellular mechanism. Oxygen free radicals and their metabolites are together termed as reactive oxygen species (ROS). Though, oxidation in DNA is a normal and unremitting process, it results in oxidative stress when disturbed by free radicals and causes damage to DNA, cellular lipids and proteins which in-turn results in cellular dysfunction and ultimately, cellular death. Usually protection from DNA damage is provided by chromatin.

Oxidative stress takes place due to revelation to toxic agents, through tissue injury or disease or through environmental air pollution. Thus, oxygen from both internal and external sources can destroy the defense mechanism thus promoting the occurrence of mutagenesis. Rigorous and prolonged exposure to oxidative stress can bring out all stages of carcinogenesis. (Guyton and Kensler, 1999).

4. Free Radicals involvement in Carcinogenesis: Recent research has identified the involvement of oxygen free radicals in cancer promotion. (Slaga, T. J. 1983). Researches based on the experiments performed on the rat skin states that, cancer development undergoes two different stages; initiation and promotion. Initiation includes basic modification in the cells, by genetically altering them. During initiation the cells undergo chemical changes resulting in genetic transformation which is non-fatal.

Throughout initiation stage the cells lies dormant until it is been induced by free radicals (tumor promoter). Once after exposed to free radicals the cells start multiplying rapidly and start developing tumor. Finally, tumor promoters damage the defense mechanism and induce propagation of chemically altered cells thus resulting in cancer. Generally, cancer induction is caused by metal induced free radicals, or chemical carcinogens, or foreign bodies, or hereditable mutation, or hormonal changes etc. The paper would explain the role of above mentioned free radicals in inducing carcinogenesis.

4.1. Role of Hydroxyl radical (-OH): It is empirically proved that interaction of free radicals like hydroxyl radical (-OH) with DNA causes mutagenesis. A method called electron paramagnetic spectroscopy has been used to detect the involvement of hydroxyl radical in oxygen induced DNA damage. Hydroxyl radical chaotically reacts with all components of DNA molecule causing genetic lesion and thus resulting in DNA damage.

The chemicals such as super oxide ion, hydrogen peroxide which is produced during the cellular processes involves in destruction of enzymes and thus resulting in oxidative stress and DNA damage. McCord and Fridovich have proved that hydrogen peroxide and oxygen are outcome of superoxide dismutase (SOD). Superoxide which acts as a reducing agent can readily react with any compounds by easily penetrating through anion membranes. In similar way hydrogen peroxide also penetrates through membrane and reacts with superoxide in the presence of ferrous and copper ions and produces hydroxyl radical •OH. This reaction is named as Fenton reaction.
→ O2ˉ Fe (III) •OH
O2 Fe (II) H2O2 ←

Thus, hydrogen peroxide and superoxide do not directly interact with DNA to produce oxidative damage (Breimer, 1990), but they interact with transition metals like copper and ferrous to produce hydroxyl radical (•OH radical) which in-turn is responsible for DNA damage. However, Cu (II) or Fe (III) is required to be reduced before its reaction with H2O2. Fe (III) is reduced to Fe (II) either by ascorbate or sulf-hydryls or by free radicals from xenobiotics. Later these reduced metals react with H2O2 to produce oxidative damage. Hence, it is clear that metal (Fe or Cu) reduction and later metal-catalysed reduction of H2O2 are the main cause for oxidative damage in DNA.

However, evidence proves that metal chelators like other detoxifying agents blocks the enhancement of hydroxyl radicals and restrain DNA damage, mutation and malignant transformation which is induced by active oxygen species in free cells and in cellular system. (Aruoma et al. 1989).

4.2. Role of Metal Induced Oxygen Free Radicals: Few metals are omnipresent; these metals are well-known to cause mutation in human beings and in turn lead to cancer. Researches have identified some of these metals as human carcinogens (LARC, 1990).

Consumptions of transition metals can induce the formation of reactive oxygen species. In general, metal ions do not form any adductive bonds with DNA to produce mutagenesis, but in turn interacts with reactive oxygen species (ROS) producing reactive chemicals which act as a cause for mutation (Kasprzak KS, 1991). Reactive oxygen species are naturally formed in the body through cellular process or through pathological conditions such as ischemia, inflammatory conditions etc. In this paper let us focus on few such metals which are involved in destruction process resulting in pathological conditions.

4.2.1. Role of Arsenic: Recent researches has proved the involvement of Arsenic in producing toxicity through the generation of Reactive Oxygen Species like Hydrogen peroxide and other free radicals such as superoxide, hydroxyl (•OH) and preoxyl (ROO) radicals. (Peng J, Jones GL, Waston K. 2000). Arsenic is widespread in nature and it is transported through water. (Cullen WR, Reimer KJ).

Toxicity of Arsenic is due to its ability to bind with Sulfhydryl (SH) groups, especially vicinal thiols in proteins and its ability to substitute phosphate in enzyme-catalysed reactions thus resulting in dysfunction of enzyme activity. (Aposhian HV, 1989). Chronic exposure of Arsenic results in oxidative stress and increases the Level of Lipid Peroxide (LPO) by increasing the level of Inorganic Arsenic (iAs) and its methylated metabolites in blood. Also elevated level of Arsenic depletes the non-protein sulfhydryl (NPSH) in blood through different mechanism.

4.2.2. Role of Chromium: Chromium is a proved carcinogen which is widely used in industrial chemicals (Stohs SJ, Bagchi D, 1995). “Research has proved that industrial workers exposed to chromium are at higher risk to respiratory cancer than the others (Langard S, 1990)”. Ch III is a highly reactive compound which interacts with DNA and damages the strands and protein cross link and modifies the DNA base by formation of 8-hydroxydeoxyguanosine (8-OH-dG) (Snow ET, 1991). The formation of (8-OH-dG) in DNA leads to conversion of G to T base in DNA strands. (Cheng KC, Chaill DS, Kasai H, Nishimura S, Loeb LA, 1992).

This transformation due to 8-hydroxygunaine in DNA strands often results in cancer development. (Floyd, R. A, Schneider, J. E, 1990) Chromium due to its carcinogenetic nature produces extremely toxic hydroxyl radicals (•OH) from H2O2 through a Fenton-type reaction along with 8-OH-dG resulting in oxidative DNA damage (Shibutai S, Takeshita M, Grollman AP, 1991) (Lloyd DR, Carmichael PL, Philips DH, 1998). Free radicals inhibitors such as melatonin, ascorbate, and vitamin E (Trolox) restrain the formation of 8-hydroxydeoxyguanosine (8-OH-dG). Earlier studies have proved that melatonin (an antioxidant) is highly effective in inhibiting various free radicals and prevents DNA from oxidative damage.(Seweryenk E, Ortiz GG, Reiter JJ, Pablos MI, Melchiorri D, Daniel WMU, 1996), (Vijayalaxmi, Reiter RJ, Herman TS, Meltz M).

4.3. Hormones as Free Radicals in Prostrate Cancer: Researchers suspect estrogen as a causative agent in Prostrate Cancer in men. Though estrogen is a female hormone it is also present in smaller amounts in men. Estrogen produces a compound which is a powerful source of free radicals during its molecular process. Even as a fact the estrogens are hormones; it becomes carcinogenic after drop in testosterone levels where some androgens are also converted to estrogens.

Hence in older age men are highly prone to Prostrate Cancer. (Joachim G. Liehr). Meanwhile, researchers at university of Missouri _ Columbia are researching the possibilities of estrogen compounds such as metal food cans and hormones from meat and its products in association with Prostrate Cancer. (Frederick von Saal, Professor of Reproductive Biology and Neurobiology).

5. Role of Antioxidants: Antioxidants generally balance the formation of free radicals or repair the damage caused by the free radicals in the human body. Antioxidants are generally acquired from food. According to Ralph W. Moss, Vitamin C an antioxidant, reduces the risk of cancer and prevents the immune system from free radical and increase the strength of the defense mechanism. Researches have identified that lower intake of antioxidants would possibly result in cancer. Low consumption of vitamin c would result in cancer in mouth, esophagus and pancreas. (Williamson and Wyandt).

Polyphenols a strong antioxidant which is present in tea is also effective in controlling cancer. Journal of the National Cancer Institute, 2000 has published that, consumption of quercetin and naringin flavonoids reduce the risk of lung cancer. Another study by Spiker from University of Arizona has identified that the presence of higher level of antioxidant glutathione peroxidase can prevent prostrate cancer. Hence it is very clear that antioxidants act as a defense mechanism in protecting the human beings from free radicals damages which leads to cancer.

6. Measuring oxidative DNA damage: ORAC (oxygen radical absorbance capacity) is a distinctive and effective method used for measuring the level of anti-oxidant which protects cells from oxidative damage. (Guohua Cao). Oxygen Radical Absorbance Capacity measures the ability of anti-oxidant in inhibiting free radicals and the period of inhibition. This analysis provides precise measurements for different kind of antioxidants with varied strength.

7. Conclusion

In past few years researchers are involved in the process of analyzing the role of oxygen free radical in damaging DNA causing mutation which then leads to cancer and other diseases. The involvement of free radicals in the process of tumour promotion is clearly evident. Apart from the free radicals discussed in this paper there are several other free radicals involved in the process of tumor promotion in human beings. In today’s world, cancer initiation can be prevented at its initial stage by the availability of high end technologies and medical advancement. Moreover adequate intake of antioxidants would provide natural defense against the free radical damages.

8. References
1. Halliwell B, Gutteridge JMC, 1989. “Free Radicals in Biology and Medicine’, 2nd ed. Oxford: Clarendon Press.

2. Goodyear- Brunch C, Pierce JD, 2002. “Oxidative stress in critically ill patients”. Am J Crit Care, 11:543-551.
3. Kohen R, Nyska a, 2002. “Oxidation of Biological Systems: Oxidative Stress Phenomena, Antioxidants, Redox Reactions, and Methods for their Qualification”. Toxicol Path, 30(6):62650.
4. Kohen R, Nyska a, 2002. “Oxidation of Biological Systems: Oxidative Stress Phenomena, Antioxidants, Redox Reactions, and Methods for their Qualification”. Toxicol Path, 30(6):62650.
5. Kasprzak KS, 1991. “The Role of Oxidative Damage in Metal Carcinogenicity”. Chems Res Toxicol 4:604-615 (1991).
6. Aposhian HV, 1989. “Biochemical Toxicology of Arsenic”. Rev Biochem Toxicol 10:265-299.
7. Stohs SJ, Bagchi D, 1995. “Oxidative Mechanism in the Toxicity of Metal Ions”. Free Radic Biol Med 18:321-336.
8. Langard S, 1990. “One Hundred Years of Chromium and Cancer: A Review of Epidemiological Evidence End Selected Case Reports”. Am J Ind Med 17:189-215.
9. Shibuttai S, Takeshita M, Grollman AP, 1991. ‘”Insertion of Specific Base During DNA synthesis Past the Oxidation-Damaged Base 8-oxo-dG”. Nature 349:431.
10. Lloyd DR, Carmichael PL, Phillips DH, 1998. “Comparison of formation of 8-hydroxy-2-deoxyguanosione and Single-and Double-Strand Breaks in DNA Mediated by Fenton Reaction”. Chem Res Toxicol 11:420-427.
11. Snow ET, 1991. “A Possible Role for Chromium (III) in Genotoxicity”. Environ Health Perspect.

9. Bibliography

1. Horvitz, Leslie Alan. 1997. ‘Doctors Continue to Differ Widely on Treatment for Prostrate Cancer’. Insight on the News, 16 June, 38+.
2. Mcbride, Judy. 1999. ‘What is ORAC?’ World and I, July, 178.
3. Pi, Jingbo, Hiroshi Yamauchi, Yoshito Kumagai, Guifan Sun, Takahiko Yoshida, Hiroyuki Aikawa, Claudia Hopenhayn-Rich, and Nobuhiro Shimolo. 2002. ‘Evidence for Induction of Oxidative stress Caused by Chronic Exposure of Chinese Residents to Arsenic Contained in Drinking Water’. Environmental Health Perspectives, 110, no. 4: 331+.
4. Xu, An, Hongning Zhou, Dennis Zengliang Yu, and Tom K. Hei. 2002. Mechanisms of the Genotoxicity of Crocidolite Asbestos in Mammalian Cells: Implication from Mutation Patterns Induced by reactive Oxygen Species’. Environmental Health Perspective. 110, no. 10: 103+.

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