SUPEROXIDE DISMUTASE – EVIDENCE BASED PERSPECTIVES

TO TARGET THE REDOX DYSREGULATION: UPDATE 2013Dr Navneet Wadhwa *, Dr Hemant Thacker **

*MD (Pharmacology) Deputy General Manager, Medical Services, Alkem (Bergen), Mumbai ** MD (Medicine), FACE. Sr Consultant Physician and Cardiometabolic specialist, Bhatia Hospital, Jaslok Hospital, Breach Candy Hospital Mumbai, India

BACKGROUND

Reactive oxygen species (ROS) including superoxide radicals are attributed for the pathogenesis of various diseases

The reactive intermediate generated by the utilisation of oxygen impairs the functioning of cells and tissues. Superoxide dismutase (SOD) catalyzes the conversion of single electron reduced species of molecular oxygen to hydrogen peroxide and oxygen

There are several classes of SOD that differ in their metal binding ability, distribution in different cell compartments, and sensitivity to various reagents

Removal of ROS by exogenous SODs could be an effective preventive strategy against various diseases. Improvements in SOD formulation overcome the limitation of the exogenous SODs and enhance the therapeutic properties

Views of oxidative stress and redox imbalance have broadened considerably, as these conditions are now often seen as imbalances that have origins in our genes

Transcription factor called nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is referred to as the 'master regulator' of the antioxidant response, modulating the expression of hundreds of genes, including the antioxidant enzymes. Hence, dysregulation of Nrf2-regulated genes provides a logical explanation for the apparent associations between observable oxidative stress and perhaps 200 human diseases involving these various physiological processes

Fig 2: Cumulative numbers of publications retrievable by PubMed.gov on the topics of ''superoxide,'' ''oxidative stress,'' and ''redox signaling.''

Fig 1: Mechanism of oxidative stress induction. An impaired balance between ROS production and antioxidant defences results in the accumulation of oxidative products (adapted from Carillon J et al; Pharm Res. 2013 Nov;30(11):2718-28)

Although superoxide and SOD are closely related to oxidative stress, the usage of the term ''oxidative stress'' in the literature has not tracked with superoxide. The term began to appear in the 1970s, coincident with superoxide and SOD, but didn't seem to catch on until around 1995, at which point it took off with a vengeance, quickly surpassing references to superoxide and SOD. This may be explained by that the broader term ''oxidative stress'' had wide appeal to nearly all disciplines within the biological sciences, as well as to the wider medical community

Cumulative number of papers published since 1968 concerning all aspects of superoxide now exceeds 76,000

The chelating potential of exogenous SODs may partly explain the decrease of oxidative stress and inflammation observed after SODs supplementation. However, SODs half-life is only a few minutes in blood circulation, but more long effects were observed after SODs administration. Moreover, beneficial effects appears after SODs oral supplementation although SODs cannot be absorbed, which suggest that exogenous SODs have an additional influence independent of the antioxidant activity

METHODS

We searched electronic databases (Medline, Pubmed) identify and study peer reviewed case studies, observational studies, case control and cohort studies using the specific MeSH and text 'Superoxide dismutase', 'Oxidative stress' and 'redox dysregulation'. Bibliographies of retrieved papers for additional references were also hand searched and included for analysis.

RESULT

Prof Irwin Fridovich, currently Professor emeritus of Biochemistry at Duke University, North Carolina, USA can rightly be called as the 'father of SOD'; with 51,000 citations in the scientific literature, including 7 papers with >1000 citations, and an H-index of 97

He along with his student Joe M. McCord, discovered 'superoxide dismutase' on April 4, 1968

SOD was introduced to the biochemical community in an oral abstract presented at the 1969 FASEB (Federation of American Societies for Experimental Biology) meeting, followed by highly cited Journal of Biological Chemistry article that provided an assay technique that is even still widely used.

Various causes (smoking, alchohol, radiations,pollution, stress, ageing, unbalanced lifestyle...)

NADPH oxidaseXanthine oxidaseRespiratory chain

O2

_0O2

SODH O2 2

CAT

GPx0OH

0RO2

ROOH

0RO

H O2

Oxidative damage(DNA, proteins, lipids)

Various diseases

120000

100000

80000

60000

40000

20000

0

Cum

ulat

ive

publ

icat

ions Oxidative stress

Superoxide

RedoxSignaling

1960 1970 1980 1990 2000 2010Year

The first paper which identified superoxide dismutase was published in the year 1969, ever since a total of 53,986 research papers have been published till date, of which 4147 research papers have been published only in last one year.

Till date, 1060 clinical trials have been published, of which 610 have been conducted under randomized controlled setting. 279 case reports, 27 meta-analysis have been published. 3797 papers from India have been published of which 52 are been clinical trials.

Table 1. Superoxide Dismutase- Published Strength of Evidence *

Number of published evidences since 1969

More than 50,000 papers till date, of which 1000 clinical studies have been published, approx 60% of them have been conducted under randomised controlled clinical trial setting (the highest level of evidence)

Hence, concept is well researched ever since first paper was published, consistently for more than 4 decades back, starting in 1969 with publication of first research work

A lmost, every 1 in 10 paper published over last 5 years on SOD has been from India. Hence, substantial Indian data exists

In 2013 alone, till Aug 2013, approx 8000 papers have been published

Figure 4. Superoxide Dismutase- Recent Publications **Analysis as of Aug 2013

Figure 5. Superoxide Dismutase from Melon- Recent Publications**Analysis as of Aug 2013

B ernard Babior in 1973 discovered that phagocytosing polymorphonuclear leukocytes produced superoxide during the respiratory burst through the NADPH oxidase, as a bactericidal agent, which led to the understanding of the cause of chronic granulomatous disease, as a genetic defect in the NADPH oxidase. This opened the door to recognizing the useful contributions of superoxide production

Specific protective effects have been observed against irradiation, carcinogenesis, apoptosis and neurodegeneration. SODs administration alleviate inflammatory, infectious, respiratory, metabolic and cardiovascular diseases and genitourinary and fertility disorders. Role of SODs has been particularly described for modulation of various diseases including, hypertension, diabetes, familial amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, vitiligo, Oral Submucous Fibrosis, Oral Leukoplakia, dengue fever Down's syndrome, osteoarthritis, and ageing. For example- Down syndrome patients display an increased Cu/Zn-SOD/GPx and CAT activity ratio

Figure 6. Extramel® M coating guarantees SOD bioactivity

A n increase in endogenous antioxidant enzymes after exogenous SODs administration has been demonstrated in several published reports. The induction of endogenous antioxidant defence with a decrease in oxidative stress, explain all the effects observed and could be an important element to explain the cause effect relationship.

CONCLUSION

SODs enzymatic pathway is a well researched concept encompassing the entire spectrum from healthy to various disease states

SOD as an exogenous source is an emerging therapeutic option with wide therapeutic applications

The precise role of the free radicals and the need to counter the high oxidative stress to alleviate the diseased states in now better understood, which has the potential to transform the benefits of translational medicine

The quantum and the level of evidence for SOD is accelerating rapidly

Bibliography

1. McCord JM and Fridovich I. Superoxide dismutase: an enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244: 6049–6055, 1969

2. McCord JM, Fridovich I (1969). "Superoxide Dismutase, An Enzymic Function for Erythrocuprein (Hemocuprein)". Journal of Biological Chemistry 244 (22): 6049–6055

3. Fridovich I (1998). "The trail to superoxide dismutase". Protein Science 7: 2688–2690

4. Carillon J, et al; Pharm Res. 2013 Nov;30(11):2718-28

5. McCord JM, Fridovich I; Antioxid Redox Signal. 2013 Sep 11

6. Milesi MA; Nutr J. 2009 Sep 15;8:40

7. Noor R et al; Med Sci Monit, 2002; 8(9): RA210-215

8. McCord JM. The evolution of free radicals and oxidative stress.Am J Med. 2000;108:652–9.

9. Kadrnka F. Results of a multicenter orgotein study in radiation induced and interstitial cystitis. Eur J Rheumatol Inflamm.1981;4(2):237–43

10. Baret A et al; Pharmacokinetics and anti-inflammatory properties in the rat of superoxide dismutase (CuSODs and MnSOD) from various species. Biochem Pharmacol.1984;33(17):2755–60.

*Analysis as of Aug 2013

Research publication

53986

Review articles

2397

Clinical Trials

1060

Randomised Trials

610

Meta analysis

27

12000

10000

8000

6000

4000

2000

0

7790

740

2013 2012 2011 2010 2009

10617

1066 739

7457

6164

566 593

7176

Overall publications

Indian publications

18

16

14

12

10

8

6

4

2

0

5

2013 2012 2011 2010 2009

14 1416 16

SO

D p

lasm

a co

ncen

trat

ion

(U/m

L)

400

360

320

280

240

200Control

+37.5%

®SOD by Bionov

Fig 3: SOD B® Original mechanism of action

In the cell:

EndogenousSODGpxCAT

Oxidative stress and inflammation

Beneficial effects in several situationsNo intestinal absorption

Year

No.

of

publ

icat

ions

Year

No.

of

publ

icat

ions