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Oxidative Stress and Thyroid Secretions – A Review

by Dr Mohan Krishnarao Kale(more info)

listed in stress, originally published in issue 119 - January 2006


Oxidative stress arises when highly reactive free radicals produce oxidative damages to the macromolecular structures of the cell. Every cell requires radicals for its routine biochemical processes. However, it is extremely difficult for a cell to generate only the required number of radicals so that none remains unutilized. Therefore, every cell has evolved an antioxidant defense mechanism, which normally takes care of excess radicals and prevents consequent oxidative damage. In the event of overwhelming radicals, the available antioxidant defence falls short and unscavenged radicals remain free, which eventually oxidizes essential components of cell viz. DNA, proteins and membrane bound lipids. Such a condition is normally referred to as oxidative stress.

The stimulation of any cell, either electrically or through any ligand, transmembranely activates the redox system to produce the higher number of radicals, so that the increased energy can be extended to the biochemical processes to support the physiological function of the cell. Occasional stimulation of any cell may not lead to oxidative stress, unless the antioxidant defense is extraordinarily restricted. However, continued activation over a long period may cause oxidative stress.

The inherent capacity of a cell to generate radicals depends upon the frequency of activation, biochemical turnover and the nature and extent of work to be performed. This holds good until there is perfect coordination between external stimulation, the biochemical response and the work output. In event of ageing, there is an imbalance in these parameters and the generated-radicals initiate apoptosis through the oxidation of essential components. However, some specialized cells, such as the macrophages, are exceptional in that they are particularly designed to generate excess free radicals so as to oxidatively kill the engulfed microorganism.

Factors causing Excessive Stimulation of Cell

Though there are diverse factors or stimuli that can influence the cell to perform more work, all of them can be grouped together and named stressors. They can be called stressors because all of them directly or indirectly alter the homeostasis and the state of allstasis which is stressful to the body.

An adverse effect is in fact a simple biochemical Stress. It is a force that disrupts equilibrium or produces strain or affects normal homeostasis. Stress can be defined as a state of threatened homeostasis. Hans Selye deserves much of the credit for introducing this term stress. A stressor may be viewed as a stimulus that disrupts homeostasis. When a person cannot handle stress, it produces pathological changes. These changes lead to Oxidative Stress. The thyroid hormones may play a crucial role in inducing the generation of generalized Oxidative Stress.

Types of Stress:

1 Psychological Stress due to anxiety, fear, frustration, restrain, isolation, etc;
2. Physiological Stress or metabolic stress due to abnormal metabolism;
3. Environmental Stress due to pollution, radiation, electromagnetic field, etc;
4. Physical Stress due to cold, heat, intense radiation, noise, vibration, etc;
5. Chemical Stress due to poisons, chemicals, drugs, medicines, etc.
The literature has demonstrated that most of the above stressors have been identified to generate free radicals.[1][2][3][4]

Free Radicals

Free radicals are molecules that are over-reactive because they are unbalanced electronically (they contain an unpaired electron). Addition of an unpaired electron to the molecule often makes it highly unstable and reactive.

Some situations when free radicals are produced

Controllable amounts of free radicals are formed during normal cellular functions, but excess free radicals can result from drugs, air pollution, tobacco smoke, pesticides, herbicides, chemicals in our food and water, allergic reactions, emotional upsets, excessive exercise, and even an excess of certain dietary substances such as fats. As such, free radicals can be formed in the following three ways.[5]

1. By the homolytic cleavage of a covalent bond of a normal molecule with each fragment retaining one of the paired electrons;
2. By the loss of a single electron from a normal molecule;
3. By the addition of a single electron to a normal molecule.

Free Radicals: Patho-physiology

Free radicals try to gain stability by capturing an additional electron from the molecule of the surrounding structures, so that the unpaired electron can become paired. The process of capturing an electron involves reacting with 'donor' molecule, which loses an electron and is said to have been 'oxidized'. This oxidized donor molecule then has the capacity to oxidize other molecules, and thus set-up a chain reaction that potentially leads to damaging surrounding tissues. The free radical species formed in the body may be oxygen derived, reactive oxygen species (ROS) or nitrogen derived, Reactive Nitrogen Species (RNS). The oxygen derived species include Super Oxide (O2), Hydroxyl (HO), Hydroperoxyl (HO2), Peroxyl (ROO), Alkoxyl (RO) as free radicals and Hydrogen Peroxide (H2O2), Hypochlorous Acid (HOCL), Ozone (O3) and Singlet Oxygen as non radicals. Similarly, the nitrogen derived species are mainly Nitric Oxide (NO), Nitrogen Dioxide (NO2), Peroxynitrite Anion (ONOO) and Dinitrogen Trioxide (N2O3). Radical reactions are chain reactions. The radicals are generated in a single step or steps called initiation. They participate in a sequence called propagation reactions in which their number increases. Finally the process called termination destroys them.[5]

Once formed, these highly reactive radicals can start a chain reaction, like dominoes. In the attempt to become balanced, they rob electrons from the molecules that make up the cells in your body, damaging or destroying them. Their chief danger comes from the damage they can do when they react with important cellular components such as DNA, or the cell membrane. Cells may function poorly or die if this occurs. Lipid peroxidation has been implicated in a wide range of tissue injuries and diseases. Proteins and nucleic acids appear less susceptible than PUFAs to free radical attack in that there seems less possibility of rapidly – progressing, destructive chain-reactions being initiated.

First Line of Defense (Enzymatic Antioxidant)

The first lines of Defence against O2 and H2O2 mediated injury are antioxidant enzymes: Superoxide Dismutase (SOD), Glutathione Peroxides (GPx) and Catalase (CAT).

Second Line Of Defence: Radical Scavenging Antioxidants

The antioxidants belonging to second line defense include Glutathione (GSH), Vitamin C, Vitamin E (mainly a-tocopherol), Uric acid, Albumin, Carotenoids, and Flavonoids.

Oxidative Stress and its Consequences

When generation of free radicals and other reactive oxygen species overwhelms the endogenous antioxidant defence of the body, the condition is called oxidative stress. This oxidative stress has been implicated in a variety of pathological conditions such as Diabetes Mellitus, Inflammation, Cancer, Ageing, Ischemia, Atherosclerosis, Liver Damage, etc.[6][7][8][9][10][11]

Thyroid Gland

The thyroid gland consists of two lobes that lie on each side of the trachea, just below the Adam's apple. It is one of the largest and most sensitive endocrine glands in the body. This unique mass of specialized tissue produces the thyroid hormones thyroxin (T4) and triiodothyronine (T3), the primary regulators of human metabolism. Both hormones are classified as biogenic amines and are derived from the amino acid, tyrosine.

Because it controls the body's metabolic rate – and the rate at which energy is produced – imbalances of thyroid hormones can have a profound effect on an individual's energy levels. Thyroid hormones accelerate cellular reactions and increase oxidative metabolism. By stimulating enzymes that control active transport pumps, demand for cellular oxygen increases, and as ATP production goes up, heat is produced. This creates a thermoregulatory effect, which increases body temperature. Basal Metabolic Rate (BMR) is directly influenced by thyroid hormone chemistry.

Effects of Thyroid Hormones

Thyroid hormones can target, influence and alter the metabolism of virtually every cell in the body.

Thyroid hormones stimulate protein synthesis and increase the rate at which triglycerides are broken down (lipolysis). This is why they are sometimes taken by athletes in sports where physical appearance is judged, especially during the final stages of pre-contest dieting. At appropriate levels, these hormones help preserve muscle and reduce body fat, but when used incorrectly or excessively, they are highly destructive to muscle (catabolic). The thyroid secretes about ten times as much T4 as T3; however, T3 is roughly two to three times more potent. Thyroxin is converted into the more active triiodothyronine with the selenium-dependent enzyme 5'-deiodinase. T3 and T4 are lipid-soluble and combine with special transport proteins upon release into the blood serum, called thyroxin-binding globulins (TBG). Less than one percent of thyroid hormones travel unattached in their free state.

During growth, thyroid hormones provide an anabolic influence on protein metabolism. This is due to their influence on insulin secretion. T4 and insulin also connect in the liver, where they mutually affect IGF activity. IGF (insulin growth factors) are powerful muscle building control agents. In the absence of adequate levels of thyroid hormones, human growth hormone (hGH) also loses its growth-promoting action and is not secreted normally.

Thyroid Pathology

Acceleration of the basal metabolic rate and the energy metabolism of tissues in several mammalian species represents one of the major functions of thyroid hormones.[12] Accumulating evidence has suggested that the hypermetabolic state in hyperthyroidism is associated with increases in free radical production and lipid peroxide levels,[13][14] whereas the hypometabolic state induced by hypothyroidism is associated with a decrease in free radical production[15] and in lipid peroxidation products.[16] However, it is not clear whether thyroid hormone induced increase in lipid peroxidation is confined to some tissues. Zaiton et al[17] found such an increase in slow oxidative but not in fast glycoltic muscle of the cat. Asayama et al14 found it in heart and slow oxidative muscle (soleus) but not in fast glycoltic muscle and liver of the rat. On the contrary, significant increase of lipid peroxidation was found by Fernandez et al[18] in the liver of hyperthyroid rats. Also the response of the antioxidant systems to both hypothyroidism and hyperthyroidism is unclear. The changes in the levels of the scavengers a-Tocopherol,[19][20] Glutathione[13][21] and Coenzyme Q,20 and activities of antioxidant enzymes[14] in various tissues were found to be imbalanced and often opposite. Furthermore, there is disagreement on the effect of hyperthyroidism on liver levels of Glutathione Peroxidase, which has been reported to both decrease[14] and increase.[21] On the other hand, the variety of substances capable of scavenging the different species of free radicals, and the complexity of the intracellular network of various antioxidants, make it difficult to understand the overall protective efficacy of the cellular defence system.

Also the research evaluated the extent of peroxidative processes in liver, heart and skeletal muscle (gastrocnemius) of rats in different thyroid states, by using indices of the tissue levels of malondialdehyde (MDA) and hydroperoxides (HPs). The effects of an altered thyroid state on antioxidant defences and susceptibility to oxidative challenge were also assessed. For this purpose, the activities of Glutathione Peroxidase and Glutathione Reductase, the vitamin E content, the overall antioxidant capacity and the response to oxidative stress in vitro of the tissues were determined.[22]

Role of Thyroid Gland in Induction of Oxidative Stress

Despite the fact that many research articles have been written about stress, stress-related diseases and oxidative stress, etc., very little work has been done to indicate the role of thyroid in induction of oxidative stress.[23]

The body generates free radicals by cellular mechanism and/or endocrine mechanism. Many scientific studies suggest that Corticotrophin Releasing Factor (CRF) supports the neuronal system; increasing the neuronal effects may generate more free radicals. Most scientists view Stress as the situation when the hypothalamo-pituitary-adrenocortical (HPA) axis, represented mainly by elevated ACTH levels, is activated.

Others suggest that activating of other systems with or without an elevation in ACTH may reflect stress-induced disturbed homeostasis. Apart from other factors, the role of neuroendocrine response in coping with stress is well recognized. During stress response, the physiological processes play a vital role in redirecting energy utilization among various organs. The thyroid gland is the body's primary regulator of metabolism. Thyroid stimulating hormone (TSH) affect metabolism and may be affected also by the Thyroxin secretions.

Reports suggest that hyperthyroidism increases Oxidative Stress. Treatment with thyroxin produces Oxidative Stress. Oxidative Stress produces immunosuppression. Hypothyroidism causes immunosuppression.

These evidences suggest that Oxidative Stress in any diseased condition, infected condition or stressed condition may be mediated through the thyroid gland. Hence, it is contemplated that the thyroid gland plays a central role in generating generalized Oxidative Stress in diseased condition. There are merits and demerits of free radical generation. Therefore, it is postulated that thyroxin may play an important role in the induction of Oxidative Stress


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About Dr Mohan Krishnarao Kale

Dr Mohan Krishnarao Kale PhD is Professor (Pharmacology) at Sharad Pawar College of Pharmacy, Wanadongri, Nagpur, (INDIA) 441 110.   His highest Qualifications include  M. Pharm (Pharmacology) PhD. He has 27 years of administrative and Teaching experience  and is a recognized PhD Supervisor RTM  at Nagpur University, MJRP University  Jaipur and Sant Gadgebaba Amaravati University. He is the recipient of the prestigious "MPA Award" from Maharashtra Pharmacist Association, Mumbai for contribution to Pharmacy Profession. (8th  Feb.2009). He has published and received three best poster presentation awards  at  National Conventions. Dr Kale’s areas of research include: Oxidative Stress and the Thyroid,  Kidney failure and future drug development, Diabetic Complications etc. He has published many research articles in national and international journals and a book titled Pharmacology and Toxicology published by VBD Printers, Nagpur.
His associations with professional organizations include: Vice-President, APTI. Maharashtra branch. (2008-2011);  Secretary, Pharmaceutical Society of India (2003-2011);  Secretary NYSS - NCP alumni association , Secretary RTMNU - UDPS alumni association.
Dr Kale may be contacted via

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