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Science Tribune - Article - March 1999

http://www.tribunes.com/tribune/art99/ray.htm

Stress - From fiend to friend




P. K. Ray


Immunotechnology Section, Bose Institute, P-1/12, CIT Scheme VII-M, Calcutta 700 054, India.
E-mail : pkray@boseinst.ernet.in


Any deviation from "normal" physiological functions may be considered stressful to the body; any agent causing a deviation is a stress-inducer or stressor (a). When stresses reach a certain theshhold, they may even threaten vital processes.


Environmental stress

Our daily life continually exposes us to agents of potential physiological stress and our modern lifestyle does little to reduce them. The air we breathe, the water we drink and the food we eat contain an ever greater number of chemicals. To combat discomfort and disease, we ingest drugs with toxic, carcinogenic, teratogenic, mutagenic, and immunosuppressive effects. All these stresses can cause organ dysfunction and disorders in metabolism, biosynthesis, immunoneurological function or in the ability to repair cell and tissue damage. Many illnesses (b) might be related to the toxic effects of environmental stressors.

Under normal circumstances, the damages caused are balanced by repairs that help maintain the body's 'homeostasis' (equilibrium) that is vital to life. Indeed, homeostasis is the reason why, most often, we do not succumb to the adverse effects of the many stressors to which we are exposed.


The evolution of stress resistance genes

How stress resistance genes evolved has long preoccupied scientists. According to the Darwinian dogma of "survival of the fittest", regulation may have developed slowly over millions of years at the genomic level to make the organism self-sustainable and fit to survive ; the genes would have been selected in the face of stressful conditions in order to save the host species and thereby the gene itself. This is maybe how the so-called 'Stress Resistance Gene' superfamily evolved. Organisms in which genes to combat stress were not selected may have gone extinct.

In the light of this hypothesis, it is highly likely that not just one or two stress resistance genes developed but a whole array of genes encoding for proteins with specific functions, e.g. enzymes, hormones, cytokines, lymphokines, biotransformation and detoxification enzymes, repair enzymes, antibody molecules, heat-shock proteins, chaperones, messengers of the signal transduction pathway, transcription factors, transactivating elements, DNA binding proteins, etc. Nature must have selected such genes so that they would be expressed in an orchestrated manner under circumstances where the organism required protection from adverse conditions. Beneficial mutations were conserved across species barriers. The advantages, from an evolutionary standpoint, converged and were retained in new genes to meet newer, greater needs. For these new genes to function economically in higher organisms, they were set up as a cascade. If any one gene was activated by a stressor to yield a multiplicity of adverse effects, the organism was able to combat these effects using the products of not one, but several,linked genes.


The body's intrinsic stress resistance

Although the human body can cope with a certain amount of stress and repair some damage, it fails to do this beyond a certain threshold. When intrinsic mechanisms fail, toxicity begins.

The major physiological stress resistance systems are :
- the biotransformation and detoxification systems (also known as phase I and phase II biotransformation systems); they act through hydrolytic, reductive and oxidative enzymes present in the microsomes of liver and other tissues and convert compounds into an excretable form,
- the bioelimination system which removes toxic and unwanted biomolecules, cellular debris etc. from the body.

On entry into the body, chemicals are transformed into short-lived, but highly reactive, electrophilic and nucleophilic intermediates (c). Normally, these are reduced by glutathione-S-transferases and glutathione into forms which are then conjugated and ultimately converted into mercaptouronic acid, glucuronides etc. In fact, the conjugation reactions convert hydrophobic molecules into hydrophilic molecules (c) that can be eliminated from the body through the kidney and urinary bladder. Blocking biotransformation, detoxification or bioelimination processes at any point would result in accumulation of intermediate toxic forms Moreover, the longer they reside in the body, the greater their toxic effect. Thus, whether toxic effects arise or not depends on whether intrinsic mechanisms, such as those depicted below, are operative at the right level.

A. Normal situation

Chemicals/Drugs Phase-I biotransformationHighly reactive toxic intermediates
Phase-II detoxification Non-toxic hydrophilic compounds, conjugates etc
Bioelemination through reticuloendothelial system, kidney, urinary bladder etc.NO TOXICITY


B. Abnormal situation (blockade)

Chemicals/Drugs (toxic)Blockade of Phase-I biotransformation reactions (fewer or less active microsomal mono-oxygenases)Large quantities of parent toxic compounds accumulate
OVERT ORGAN TOXICITY
Phase-I biotransformed highly reactive intermediatesBlockade of Phase-II detoxification reactions (less glutathione and/or glutathione-s- transferases)Highly reactive intermediate free radicals (electrophiles/nucleophiles) accumulate
OVERT ORGAN TOXICITY


C. Abnormal situation

Incompletely detoxified or untransformed toxic compounds from A and B Inefficient bioelimination because of immunodepression, less efficient kidney function and urinary bladder excretionParent compound or intermediates accumulate and reside longer
TOXICITY


The host's ability to push the reaction to the right (that is to biotransform, detoxify and eliminate) helps decrease the toxicity of the chemicals. If the required enzymes are unavailable and/or their activity is inhibited, the body falls victim to toxic insults.


Boosting intrinsic stress resistance

How marvellous, if like a car that has to be tuned up to keep running, our body could also be tuned up from time to time to keep our intrinsic ability to deal with stressful and toxic situations intact. This concept is homologous to the development of immunity against microbes (bacteria, fungi, virus, etc) when a small amount of an antigen or immunogen is innoculated to sensitize the body of the host and develop both cell-mediated and humoral immunity. Although the idea of sensitizing the host with a very small amount of a stressor does not fall strictly within the conventional concept of acquiring immunity by immunization or vaccination, it may not be a far-fetched idea for activating the host's ability to deal successfully with toxic stressors. We have observed in several studies (for review, see (1)) that the potentiation of host immune function reduces the toxicity of many chemicals.

We do not really know whether chemical resistance has anything to do with the body's immune system, but we do know that the cells of the lymphocyte-monocyte-polymorphonuclear neutrophil lineages have to be really efficient to be able to avert any toxicity due to chemicals and to mop up any damage (2). The immune system plays a vital role in the repair and reconstruction of tissues and cells damaged by toxicity and the faster the reconstruction, the more effectively the host develops tolerance against large doses of toxic chemicals.


Lessons from the past

In China and in the Indian Sub-Continent, smokers of opium, or users of other narcotics, start off by using very small amounts, the size of a seed, but gradually have to increase the dose to continue experiencing the same effect. Their organs adapt and, in time, tolerate amounts many times larger than the original dose, which, if ingested by first-time users, would make them immediately sick and might even kill them.

Similarly, an organism can adapt itself to "useful" chemicals. Many drugs lose their efficacy during long-term therapy, forcing the clinician either to increase the dosage - and alas the toxicity - or use new drugs or drug combinations. Both humans and bacteria develop tolerance to multiple drugs, causing serious public health concerns and thus inviting research into methods of enhancing the tolerance of host cells to toxic chemicals. An entirely new field, Adaptive Medicine, has emerged in recent years.

Some people can survive for months whilst fasting as Mahatma Gandhi did during the freedom movement in India. Vast numbers of poor people have to survive without food for weeks under the most unhygienic living conditions. Many populations live in the extreme heat of deserts, others in the extreme cold of Alaska or the Ladakh. All these examples indicate that the human's physiological system can adapt to highly varied and adverse conditions of stress.

Can we make use this intrinsic adaptibility to our own advantage, for our greater self-protection? Could high-risk populations, for instance those exposed to toxic chemicals in the work-place or individuals who are to undergo therapy be preconditioned, "tuned up", in order to arm them against toxic challenges ? In analogy with immunisation and vaccination, the object would be to boost repair mechanisms during preconditioning in order to cope with the cell and tissue damage caused by the toxic stressors.

Adaptive medicine is still in its infancy and answers have to be found to many questions. For instance, when can tolerance to a stress be developed, how long could this tolerance be maintained, what would be its threshhold, and how can we counter multiple and differing environmental stresses.


Biological response modifiers

Ayurvedic medicine, which is a form of medicine that has been practised for thousands of years, is based on the concept of inducing multiple responses to treat an ailment. The belief is that, when a harmful substance enters the organism, it almost always leads to more than one adverse effect and that these effects can be quite varied. A full cure can only be obtained if all these effects are repaired. Most modern drugs are designed to do a single, specific job at a time, and this might explain partial cures, relapses, secondary disorders, etc. A biological response modifier is a fairly recent term for an agent that induces several, generally beneficial, biological responses simultaneously. These agents might repair damage caused by exogenous or even endogenous substances (i.e. regenerate tissues or cells) and thus could represent a potential means of prophylaxis and treatment. It is possible that, under normal conditions, they are present in some of our foods and thus help maintain homeostasis.

Examples of biological response modifiers that have been fairly extensively studied are BCG vaccine, bacterial lipopolysaccharide, and a bacterial protein, Protein A (molecular weight 42 Kd). In laboratory mice, a very small amount (1 microg) of Protein A (for review, see 1) can stimulate immune function, significantly modify the adverse effects of biological or chemical stressors, induce an anti-tumour response, and displays antifungal and antiparasitic properties. How might it do this?

Protein A induces several biochemical responses (1) that could be considered part of a tuning up mechanism against stress. It stimulates cytochrome P450 dependent monooxygenases, potentiates detoxifiying enzyme activity, stimulates reduced glutathione production (2) (3) (4), produces increased respiratory bursts in phagocytes (5), increases superoxide dismutase and catalase activities (5), and induces nitric oxide production. It induces a Th1 type response and serves as a B cell superantigen. In so doing, it might have conferred stress resistance capability to the host since it stimulated CD4 lymphocytes, CD34 bone marrow progenitor cells, and increased CFU-erythroid and CFU-MG cell types in the bone marrow, potentiated bcl2 gene expression in normal cells but activated P53 genes in tumour cells of the same host.


Conclusion

The hypothesis that a very small amount of stress-inducing substance may alert the host to draw out its armamentarium against possible danger, and thus function as a potentiator of stress response genes, like an antigen which activates the immune response genes, is supported by evidence from several studies. Calorie restriction increases endogenous resistance against toxic and carcinogenic insults and also boosts the host's immune function (6). Preconditioning with very small amounts of various stress-inducing substances and bacterial lipopolysaccharide (LPS) protects against ischemia reperfusion-induced injury to the heart (7), (8), (9), (10). Heat-shock proteins provide resistance to various types of stress-inducing substances including alcohol (8), infectious agents etc (11)

Because we are exposed to myriads of stressors in our everyday life, such beneficial autostimulation may in fact be occurring all the time, keeping our system alert. In case of overexposure, however, a 'threshold' is crossed and the intrinsic mechanisms of the system fail.

Deliberate tuning-up of the organism might have to wait until a better understanding of the exact nature and controls of the stress resistance mechanism is possible, although successful prophylactic practices often do not require a complete understanding of genomic level mechanisms to be operational. The concept offers possibilities for developing strategies to counter the harmful effects of toxic treatments (e.g. chemotherapy and radiation therapy) in order to increase their therapeutic indexes. It might also benefit 'high-risk' populations working in contact with toxic chemicals (e.g. production, trade, waste disposal industries) or other vulnerable groups.


Notes

a. Some examples of physical, chemical and biological stressors are microgravity, radiation, electromagnetic or high-tension electric fields, hydration and dehydration, salinity, chemicals, drugs, microbes, nutrient imbalance, stressful sensory (visual, auditory, olfactory) stimuli, psychological stress, etc.

b. Examples are cancer, heart disease, infection, retardation, abortion, autoimmune disorders, mental abnormalities, etc)

c. Electrophilic: with affinity for electrons; nucleophilic: with affinity for atomic nuclei; hydrophobic: without affinity for water; hydrophilic: with strong affinity for water.


References

1. Ray PK, Srivastava M, A new concept in cancer chemoprevention. Cancer J 26, 291, 1996.

2. Ray PK, Stress genes are nature's gift for survival. Env Hlth Persp 106, A217, 1998.

3. Dohadwala M, Ray PK, In vivo protection by Protein A of hepatic microsomal mixed function oxygenase system of cyclophosphamide treated rats. Cancer Chem Pharmacol 14, 135, 1985.

4. Shanker U, Kumar A, Rao GS, Dwivedi PP, Pandya KP, Ray PK. Modulation of benzene toxicity by Protein A. Biochem Pharmacol 46, 517, 1993.

5. Mishra A, Dwivedi PD, Verma AS, Ray PK, Mechanism of enhanced phagocytic response in Protein A treated rat macrophages. Immunol Letts 34, 289, 1992.

6. Turturro A, Blank K, Murasko D, Hart R. Mechanisms of calorie restriction affecting aging and disease. Ann NY Acad Sci 719, 159, 1994.

7. Maulik N, Engelman RM, Wei Z, Lu D, Rousou JA, Das DK. Interleukin-1 alpha preconditioning reduces myocardial ischemia reperfusion injury. Circulation 88, 387, 1993.

8. Ko JK, Cho CH, Ogle CW, A correlative study on the mechanism of adaptive cytoprotection against ethanol-induced gastric lesion formation in rats. J Gastroenterol Hepatol 9, 492, 1994.

9. Deutsch T. Adaptive control in drug therapy. Acta Physiol Hungarica 82, 327, 1994.

10. Flajnik MF, Primitive vertebrate immunity: What is the evolutionary derivative of molecules that define the adaptive immune system? Ciba Found Symp 186, 224, 1994.

11. Srivastava PK, Metnoret A, Basu S, Binder RJ, McQuade ML. Heat shock proteins come of age: Primitive functions acquire new roles in an adaptive world. Immunity 8, 657, 1998.

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