Oxidative Stress and the Thyroidby Dr MK Kale*, Dr SN Umathe** and Dr KP Bhusari*

IntroductionOxidative stress arises when highly reactive free radicals

produce oxidative damages to the macromolecular structures of thecell. Everj- cell requires radicals for its routine biochemicalprocesses. However, it is extremely difficult for a cell to generateonly the required number of radicals so that none remains unuti-lized. Therefore, every cell has evolved an antioxidant defensemechanism, which normally takes care of excess radicals andprevents consequent oxidative damage, In the event of overwhelm-ing radicals, the available antioxidant defence falls short andunscavenged radicals remain free, which eventually oxidizes essen-tial components of cell viz. DNA, proteins and membrane boundlipids. Such a condition is normally referred to as oxidative stress.

The stimulation of any cell, either electrically or throughany ligand, transmembranely activates the redox system toproduce the higher number of radicals, so that the increasedenergy can be extended to the biochemical processes to supportthe physiological function of the cell. Occasional stimulation ofany cell may not lead to oxidative stress, unless the antioxidantdefense is extraordinarily restricted. However, continued activa-tion over a long period may cause oxidative stress.

The inherent capacity of a cell to generate radicals dependsupon the frequency of activation, biochemical turnover and thenature and extent of work to be performed, This holds gooduntil there is perfect coordination between external stimulation,the biochemical response and the work output, In event ofageing, there is an imbalance in these parameters and thegenerated-radicals initiate apoptosis through the oxidation ofessential components. However, some specialized cells, such asthe macrophages, are exceptional in that they are particularlydesigned to generate excess free radicals so as to oxidatively killthe engulfed microorganism.

Factors causing Excessive Stimulation of CellThough there are diverse factors or stimuli that can influ-

ence the cell to perform more work, all of them can be groupedtogether and named stressors. They can be called stressorsbecause all of them directly or indirectly alter the homeostasisand the state of allstasis which is stressful to the body.

An adverse effect is in fact a simple biochemical Stress. It is aforce that disrupts equilibrium or produces strain or affectsnormal homeostasis. Stress can be defined as a state of threat-ened homeostasis. Hans Selye deserves much of the credit forintroducing this term stress. A stressor may he viewed as a stim-ulus that disrupts homeostasis. When a person cannot handlestress, it produces pathological changes. These changes lead toOxidative Stress. The thyroid hormones may play a crucial rolein 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;

Free radicals try to gain stability by capturing anadditional electron from the molecule of thesurrounding structures, so that the unpairedelectron can become paired.

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. '" '

Free RadicalsFree radicals are molecules that are over-reactive because

they are unbalanced electronically {they contain an unpairedelectron). Addition of an unpaired electron to the molecule oftenmakes it highly unstable and reactive.

Some situations when free radicals are producedControllable amounts of free radicals are formed during

normal cellular functions, but excess free radicals can resultfrom drugs, air pollution, tobacco smoke, pesticides, herbicides,chemicals in our food and water, allergic reactions, emotionalupsets, excessive exercise, and even an excess of certain dietarysubstances such as fats. As such, free radicals can he formed inthe following three ways.'1. By the homolytic cleavage of a covaient bond of a normal

molecule with each fragment retaining one of the pairedelectrons;

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-physiologyFree radicals try to gain stability by capturing an additional

electron from the molecule of the surrounding structures, so thatthe unpaired electron can become paired. The process of capturingan electron involves reacting with 'donor' molecule, which loses anelectron and is said to have been 'oxidized'. This oxidized donormolecule then has the capacity to oxidize other molecules, and 'thus set-up a chain reaction that potentially leads to damagingsurrounding tissues. The free radical species formed in the body

24 POSITIVE HEALTH January 2006

may be oxygen derived, reactive oxygenspecies (ROS) or nitrogen derived, ReactiveNitrogen Species (RNS). The oxygenderived species include Super Oxide (02),Hydroxyl (HO), Hydroperoxyl {H02),Peroxyl (ROO), Alkoxyl (RO) as free radi-cals and Hydrogen Peroxide (H2O2),Hypochlorous Acid (HOCL), Ozone (03)and Singlet Oxygen as non radicals.Similarly, the nitrogen derived species aremainly Nitric Oxide (NO), NitrogenDioxide {N02), Peroxynitrite Anion(ONOO) and Dinitrogen Trioxide (N2O3).Radical reactions are chain reactions. Theradicals are generated in a single step orsteps called initiation. They participate ina sequence called propagation reactions inwhich their number increases. Finally theprocess called termination destroys them/

Once formed, these highly reactiveradicals can start a chain reaction, likedominoes. In the attempt to becomebalanced, they rob electrons from themolecules that make up the cells in yourbody, damaging or destroying them. Theirchief danger comes from the damage theycan do when they react with importantcellular components such as DNA, or thecell membrane. Cells may function poorlyor die if this occurs, Lipid peroxidationhas been implicated in a wide range oftissue injuries and diseases. Proteins andnucleic acids appear less susceptible thanPUFAs to free radical attack in tbat thereseems less possibility of rapidly -progressing, destructive cbain-reactionsbeing initiated.

First Line of Defense (EnzymaticAntioxidant)

The first lines of Defence against 02and H2O2 mediated injury are antioxidantenzymes: Superoxide Dismutase (SOD),Glutathione Peroxides (GPx) and Catalase(CAT).

Second Line Of Defence:Radical Scavenging Antioxidants

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

Oxjdative Stress and its ConsequencesWhen generation of free radicals and

otber reactive oxygenspecies overwhelms theendogenous antioxidantdefence of the body, thecondition is calledoxidative stress.

This oxidative stress bas been implicatedin a variety of pathological conditionssuch as Diabetes Mellitus, Inflammation,Cancer, Ageing, Ischemia,Atherosclerosis, Liver Damage, etc.^'*'^''""

Thyroid GlandThe thyroid gland consists of two

lobes that lie on each side of the trachea,just below the Adam's apple. It is one ofthe largest and most sensitive endocrineglands in the body. Tbis unique mass ofspecialized tissue produces the thyroidhormones tbyroxin {T4) and triiodothyro-nine (TS), tbe primary regulators ofhuman metabolism. Both hormones areclassified as biogenic amines and arederived from the aminc acid, tyrosine.

Because it controls the body's meta-bolic rate - and the rate at whicb energyis produced - imbalances of thyroidhormones can have a profound effect onan individual's energy levels. Thyroidhormones accelerate cellular reactionsand increase oxidative metabolism. Bystimulating enzymes that control activetransport pumps, demand for cellularoxygen increases, and as ATP productiongoes up, heat is produced. Tbiscreates a thermoregulatoryeffect, wbich increases bodytemperature. Basal MetabolicRate (BMR) is directly influ-enced by thyroid hormonechemistry.

converted into the more active triiodothy-ronine with the selenium-dependentenzyme 5'-deiodinase. T3 and T4 are lipid-soluble and combine with special transportproteins upon release into the blood serum,called tbyroxin-binding globulins (TBG).Less than one percent of thyroid hormonestravel unattached in their free state.

During growth, thyroid bormonesprovide an anabolic influence on proteinmetabolism. This is due to their influenceon insulin secretion. T4 and insulin alsoconnect in the liver, where they mutuallyaffect IGF activity. IGF (insulin growthfactors) are powerful muscle buildingcontrol agents. In tbe absence ofadequate levels of tbyroid hormones,human growth hormone (hGH) also losesits growtb-promoting action and is notsecreted normally.

Thyroid PathologyAcceleration of the basal metabolic rate

and the energy metabolism of tissues inseveral mammalian species represents oneof the major functions of thyroidhormones.'' Accumulating evidence hassuggested that the hypermetabolic

EfTects of ThyroidHormones

Thyroid hormones cantarget, influence and alter tbemetabolism of virtually every cell in tbebody.

Thyroid bormones stimulate proteinsynthesis and increase the rate at wbichtriglycerides are broken down (lipolysis).This ia why they are sometimes taken byathletes in sports where physical appear-ance is judged, especially during tbe finalstages of pre-contest dieting. At appropri-ate levels, these hormones belp preservemuscle and reduce body fat, but when usedincorrectly or excessively, they are highlydestructive to muscle (catabolic). Tbethyroid secretes about ten times as muchT4 as T3; however, T3 is roughly two totbree times more potent. Tbyroxin is

Controllable amounts of free radicalsare formed during normal cellular

functions, but excess free radicals canresult from drugs, air pollution, tobaccosmoke, pesticides, herbicides, chemicals

in our food and water, allergicreactions, emotionai upsets, excessive

exercise, and even an excess of certaindietary substances such as fats.

state in hyperthyroidism is associated withincreases in free radical production andlipid peroxide levels,'"* whereasthe hypometabolic state induced byhypothyroidism is associated with adecrease in free radical production'"and in lipid peroxidation products.'^However, it is not clear whetherthyroid hormone induced increase inlipid peroxidation is confined to sometissues. Zaiton et aF found such anincrease in slow oxidative but not infast glycoltic muscle of the cat. Asayama etal'" found it in heart and slow oxidativemuscle (soleus) but not in fast glycoltic

muscle and liver of

Free radicals try to gain stability by capturing anadditional electron from the molecule of the

surrounding structures, so that the unpaired electroncan become paired.

the rat. On thecontrary, signifi-cant increase oflipid peroxidationwas found by

POSITIVE HEALTH January 2006

26

The free radicalspecies formed in the bodymay be oxygen derived, reactiveoxygen species (ROS) or nitrogenderived. Reactive Nitrogen Species (RNS).The oxygen derived species include SuperOxide (O2), Hydroxyl (HO), Hydroperoxyl(H02), Peroxyl (ROO), Alkoxyl (RO) as free

radicals and Hydrogen Peroxide (H2O2),Hypochlorous Acid (HOCL), Ozone (O3)

^ and Singlet Oxygen asnon radicals.

Fernandez et al'" in the liver of hyperthy-roid rats. Also the response ofthe antioxi-dant systems to hoth hypothyroidism andhyperthyroidism is unclear. The changes inthe levels of the scavengers ct-Tocopherol,'^^Glutathione'^" andCoenzyme Q,20 and activities ofantioxidant enzymes" in varioustissues were found to be imbal-anced and often opposite.Furthermore, there is disagree-ment on the effect of hyper-thyroidism on liver levels ofGlutathione Peroxidase, which hasbeen reported to both decrease"and increase.^' On the other hand,the variety of substances capableof scavenging the different speciesof free radicals, and the complex-ity of the intracellular network ofvarious antioxidants. make it diffi-cult to understand the overallprotective efficacy of the cellulardefence system.

Also the research evaluatedthe extent of peroxidative processes inliver, heart and skeletal muscle (gastroc-neniius) of rats in different thyroidstates, by using indices ofthe tissuelevels of malondialdehyde (MDA) andhydroperoxides (HPs). The effects of analtered thyroid state on antioxidantdefences and susceptibility to oxidativechallenge were also assessed. For thi.spurpose, the activities of GlutathionePeroxidase and Glutathione Reductase,the vitamin E content, the overall antiox-idant capacity and the response to oxida-tive stress ill vitro ofthe tissues weredetermined/^

stress-related diseases and oxidativestress, etc., very little work has beendone to indicate the role of thyroid in

induction of oxidative stress."The body generates free radicals

hy cellular mechanism and/orendocrine mechanism. Manyscientific studies suggest thatCorticotrophin Releasing Factor(CRF) supports the neuronal

system; increasing the neuronaleffects may generate more free radi-

cals. Most scientists view Stress asthe situation when the hypothalamo-

pituitary-adrenocortical (HPA) axis,represented mainly by elevated ACTHlevels, is activated.

Others suggest that activating ofother systems with or without an eleva-tion in ACTH may reflect stress-induceddisturbed homeostasis. Apart from other

RightThyroidGland

Larynx

LeftThyroidGland

'he Thyroid Gland

Trachea

Role of Thyroid Gland in Induction ofOxidative Stress

Despite the fact that many researcharticles have been written about stress,

factors, the role of neuroendocrineresponse in coping with stress is wellrecognized. During stress response, thephysiological processes play a vital role inredirecting energy utilization amongvarious organs. The thyroid gland is thebody's primary regulator of metaholism.Thyroid stimulating hormone (TSH)affect metabolism and may be affectedalso by the Thyroxin secretions.

Reports suggest that hyperthyroidismincreases Oxidative Stress. Treatmentwith thyroxin produces Oxidative Stress.Oxidative Stress produces immunosup-pression. Hypothyroidism causesimmunosuppression.

These evidences suggest tbatOxidative Stress in any diseased condi-tion, infected condition or stressed condi-tion may be mediated through the

thyroid gland. Hence, it is contemplatedthat tbe thyroid gland plays a centralrole in generating generalized OxidativeStress in diseased condition. There aremerits and demerits of free radical gener-ation. Therefore, it is postulated thatthyroxin may play an important role inthe induction of Oxidative Stress

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4

The free radical species formed In the body may beoxygen derived, reactive oxygen species (ROS] ornitrogen derived, Reactive Nitrogen Species [RNS).The oxygen derived species include Super Oxide(02), Hydroxyl (HO), Hydroperoxyi (H02), Peroxyl(ROO), Alicoxyl (RO) as tree radicals and HydrogenPeroxide (H2O2), Hypoctilorous Add (HOCL), Ozone(03) and Singlet Oxygen as non radicals.

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About the AuthorMohan Kriahna Kale is Asst. Prof. (Pharmacology) at Nagpur

College of Pharmacy, India. He has published two books onPharmacology and Toxicology, in addition to articles in nationaland international papers. His expertise is in the field of diabeticcomplications, free radicals, oxidative stress and validationparameters. He can be contacted via kalerakncp@rediffmail.com

*Nagpur College of Pharmacy, Wanadongri, Hingna-road,Nagpur 441110. kalemkncp@rediff mail.com

**Dept of Pharmaceutical Sciences, Nagpur UniversityCampua, Nagpur 440010.

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