Role of Lithium in Living Systems-An Outlook

Role of Lithium in Living Systems-An Outlook

Satish Kumar

Associate Professor (Physics), Govt. College Jhandutta Distt. Bilaspur (H.P.)

ABSTRACT:

INTRODUCTION:

The natural level of lithium in the blood of healthy individuals has been measured (1). The value in the plasma was around 90 nano equiv/liter and in the erythrocytes around 95 nequ/liter. Thus, the distribution is approximately at unity. The doses to be established for the treatment of MDP (Manic Depressive Psychosis) are about four orders of magnitude higher in the serum and about 3 to 4 orders higher in the erythrocytes. Studies emanating from India showed average serum lithium levels of 30 nequ/liter, with a variation from 14 to 72 nequ/liter (2). A more recent study with vastly improved analytical techniques reported values of 1.8 to 4.4 nanograms/gram of dry weight (3). Assuming that the dry weight is about 5% to 6% of the total, this is an average value of about 70 nequ/liter in whole blood, a value which coincides with the one reported by the Russian authors.

Clarke et al. (3) consider the narrow range for lithium in blood as pointing to a strong indication that lithium is an essential element. Schou (4) in tum argues that the 3 to 4 order of magnitude difference between the natural level of lithium and the one required for a successful treatment of manic-depressive illness precludes the argument of essentiality.

Quantity of Lithium Ion In Vitro and In Vivo:

Manic/depressive patients are treated with lithium effectively when the serum concentration of Li+ is between 0.5 and 1.0 mM/L. Daily administration of 600 to 900 mg/day of Li2C03 (20 to 30 mM of Li+) usually achieves this goal. The average human serum volume is about 6 liters, thus there are between 3 and 6 mM of Li+ contained in the serum, or about 20% of the daily intake. The serum weight is about 10% of the weight of the human body. Thus, on the average the concentration in the remainder (or 90%).

The Consequence of Certain Membranes:

Even lower concentrations can be assumed in the adrenergic centers in the brain, because of the impediment the blood-brain barrier imposes on electrolyte transport. The Li concentration effective in a normal neural microenvironment may be quite small indeed. Could it be that it is correlated to the evolutionary "natural" presence of the element on earth?

Effects of the Lithium Ratio:

A slight change in electrolyte concentrations in this environment could prepare for significant pathological consequences. To re-establish a microenvironment where Li+ returns to its "normal" level, a very large load of Li+ is necessary in the serum. It could be that several orders of magnitude higher concentrations are demanded to obtain this objective. This is why loads of up to 1 mM/L in serum must be maintained. Regrettably this concentration is approaching toxic levels.

Location of Li+:

This toxicity can also be explained by the fact that the distribution of Li+ throughout the human body is widely varied. It is very likely that there are areas in the body where Li+ is concentrated substantially. Such areas are likely to be the triphosphate moiety of the nucleic acids, the phosphoinositol and other polyphosphatidyl systems. Enzyme complexes located in the protein phase of the proteolipid membranes with their metal ion cofactor specificity are other areas where Li+ may accumulate.

Administration versus Clearance:

One might assume that all lithium administered is eventually cleared by urinary, fecal, and perspiratory elimination. Some data exist that indicate elimination in the high 90%. If one assumes that Li is an essential element in the evolutionary context, the amounts retained by bipolar patients may correlate to a lack of very small amounts of Li, which might be the cause of these pathological conditions.

Lithium Concentration of In Vitro Antiviral Tests:

Skinner et al. (5) and Specter and Bach (6,7) have demonstrated that Li+ effectively interferes with the replication of DNA viruses in vitro. The concentration at which the interference becomes noticeable in the relatively short time span (up to 10 days) is above 10 mM/L, one order of magnitude higher than the maximum serum concentration possible before toxic side effects become noticeable.

Ionophores:

The transport of ions across biological membranes is of primary importance in most metabolic processes. In the following, literature is reviewed which deals primarily with the transport of the lithium ion. This is of tremendous interest to all who are concerned with the pharmacokinetics of lithium, mostly to psychiatrists, but also to researchers concerned with the hematopoietic, immune-enhancing, and antiviral properties of the lithium ion. It is quite apparent that in medical practice, in order to achieve therapeutic action, the bodily systems are usually loaded close to toxic levels. It is also known that lithium does not easily transgress the blood brain barrier and that the concentrations needed to bring the adrenergic/cholinergic systems into equilibrium resembling "normalcy" are one order of magnitude lower than the one created in the serum.

Lithium and the Prostaglandin:

Horrobin (8) makes the case of "paradoxical" actions of lithium in an elegant way. Inherent in his proposition is the assumption of the presence of the lithium ion in all the systems he discusses. The question is that of either excessive or deficient quantity. The main concern is with the immune systems, especially their link with the prostaglandins. The biosynthetic path leads from essential fatty acids such as linolenic acid to di homo gamma linolenic acid (DGLA) which then converts to prostaglandins by mediation of a cyclooxygenase enzyme complex.

Membranes Homeostasis:

In the case of bipolar illness, the contrast is "bipolar health," characterized by mood swings rather than by flip-flops. An equilibrium of helper and suppress Qr functions means normal immune response capabilities as well as bodily resources to ward off autoimmunities. The natural presence of trace amounts of lithium in the nanoequivalent/liter range may be one of the guarantors of this homeostasis. If the equilibrium is disturbed by external factors such as microbial and viral infections, manipulation of the lithium level in cellular and humeral environs may be a remedial option. We are very far from understanding how to handle this potential tool. Certainly, this can only be successful in the context of establishing proper ratios between the macroconstituents Ca, Mg, Na, K, CI, P, S, and Li. In addition, one cannot dismiss potential interactions with essential trace elements, such as Fe, Co, Zn, Cr, Mo, and Se, to name just a few.

Permeation of Li+ Ion in the Phospholipid Membranes:

Pandey (9,10) described the different modes of transportation of Li+ across the RBC membrane. Four different pathways are recognized: leak (which is similar to diffusion), Li+/Na+ exchange, anion exchange (LiC03_), and Na+ -K+ pump (Na/K ATPase mediated). The steady state between red cells and plasma is defined as the Li ratio, and is usually lower than unity. The concentration of Na+ determines in which direction Li+ flows across the membranes: the experiments demonstrate an uphill extrusion of Li+ from red blood cells which is driven by a Na+ gradient which mandates exchange of Na+ in the opposite direction.

CONCLUSION:

Beyond doubt, the picture emerges clearly that ionic equilibria play a very important role in this push-pull situation of bipolar illness. Not only is Li+ competing for the cofactor position of the enzyme system, it also is modifying the flux of other ions, mono and divalent, such as Na and Ca. The membrane channels are suffering alterations upon the arrival of new ionic wanderers (Hess) and these changes will allow a release of excess Na and Ca ions bottled up within the 12 RD. Bach neuronal cell, where they were creating dysfunctions. This, additionally, could account for the antimanic and antidepressive effects of the lithium ion.

REFERENCES:

1.         Fleishman, D.G., Gurevich, Z.P., Solyus, A.A., Baklanova, S.M., and Skul'skii, l.A. (1980). The natural lithium content in the blood of man and certain animals. Doklady Akademii Nauk SSSR, 254(6), 1497-1501.

2.         Jathar, V.S., Pendharkar, P.R., Pandey, V.K., Raut, S.1., Doongaji, D.R., Bharucha, M.P.E., and Satoskar, R.S. (1980). Manic depressive psychosis in India and the possible role of lithium as a natural prophylactic. II-Lithium content of diet and some biological fluids in Indian subjects. J. Postgrad. Med., 26(1), 39-44.

3.         Clarke, w.B., Webber, C.E., Koekebakker, M., and Barr, R.D. (1987). Lithium and boron in human blood. J. Lab. Clin. Med., 109, 155-158.

4.         Schou, Mogens (1989). Lithium Treatment of Manic-Depressive Illness, 4th rev ed, KARGER, Basel-Miinchen-Paris-London -New York -New Delhi-Singapore-TokyoSydney, p. 22

5.         Skinner, G.R.B., Hartley, c., Buchan, A., Harper, L., and Gallimore, P. (1980). The effect of lithium chloride on the replication of herpes simplex virus. Med. Microbiol. Immunol., 168,139-148.

6.         Specter, S., Bach, R.O., and Green, C. (July, 1986). Inhibition of herpes virus in cell cultures by lithium ions. Abstr. IXth Inter. Congo Infect. and Parasit. Dis. (p. 417) Munich.

7.         Specter, S., and Bach, R.O. (1987). Lithium ion induced inhibition of herpes-viruses in cell culture. Abstr. Ann. Meeting Am. Soc. Microbiol., 16.

8.         Horrobin, D.F. (1985). Lithium in the control of herpes virus infections. In R.O. Bach (Ed.), Lithium: Current applications in science, medicine and technology (p. 397). New York: Wiley and Sons.

9.         Pandey, G.N. et al. (1978). Lithium transport pathways in human red blood cells. The Journal of General Physiology, 72,233-247.

10.      Pandey, G.N., and Davis, 1M. (1980). Biology of the lithium ion. In A.H. Rossoff and WA. Robinson, (Eds.), Lithium effects on granulopoiesis and immune function (pp. 16-59). New York: Plenum Press.