Regulation of lithium levels in man: Is there evidence of biological essentiality?

Lithium is a ubiquitous element in our external environment and its salts have entered wide-spread use as therapeutic agents for some psychiatric disorders. Nevertheless, a fundamental biological role for the element remains to be established. In large measure this reflects the limited ability to deplete lithium selectively from experimental systems. Physiological studies have been hampered also by the previous lack of a sufficiently sensitive and specific assay for lithium in normal tissues. A method using the techniques of thermal neutron irradiation and static mass spectrometry offers a solution to the latter difficulty. Lithium levels in the blood of healthy subjects appears to be stable within geochemical domains, but the levels vary widely (more than 200 fold) between populations resident in different areas. These observations reflect the quantity of lithium ingested in the diet and water supply. The different lithium levels do not appear to be associated with any biological effects. By contrast, at levels within the therapeutic range used in psychiatric practice, 0.5-1.0 x 10^-3 M, concentrations close to those associated with predictable toxicity, lithium stimulates blood cell production, especially of neutrophilic granulocytes, both in vivo and in vitro. Evidence from studies of twins and discrete populations suggests that the concentration of lithium in human tissues is affected by genetic regulation. We propose that this is mediated by a protein ligand. Others have identified several targets for the action of lithium including intracellular G proteins, which play an important role in post-receptor information transduction, and the steroid-steroid receptor complex. The latter offers a mechanism by which lithium may influence gene expression.