Natural variations of lithium isotopes in a mammalian model

Despite lithium's extensive clinical applications, the cellular and molecular basis for the therapeutic effects remains to be elucidated. The large difference in mass between the two lithium isotopes ((6)Li and (7)Li) has prompted biochemists to explore the metabolism of Li by using pure (6)Li and (7)Li labeled drugs. However, experiments were carried out at very high Li concentrations, which did not reflect natural conditions. In the present study, we consider, for the first time, the natural variations of the (7)Li/(6)Li ratio in the organs and body fluids of an animal model, sheep. Each organ seems to be characterized by a specific Li isotope composition. So far, the range of the (7)Li/(6)Li ratio in the sheep body, expressed as δ permil variations relative to the L-SVEC standard (δ(7)Li), is about 40‰, between muscles (∼40‰) and kidney (∼0‰). Relative to a dietary δ(7)Li value of ∼+17‰, serum, red blood cells, muscle, liver, brain and kidney have a (7)Li enrichment of -12‰, -14‰, +22‰, +5‰, -3‰ and -15‰, respectively. The Li isotope composition is likely to be fractionated during intestinal absorption, with a greater absorption of (6)Li relative to (7)Li. According to previous conclusions obtained with (6)Li and (7)Li labeled chemicals, (6)Li appears to diffuse into erythrocytes faster than does (7)Li. However, this does not hold for myocytes and hepatocytes, because these two tissues have a higher δ(7)Li level than serum. Purely diffusive isotopic fractionation would leave all organs (7)Li-depleted relative to the serum, which is not the case, suggesting that active, molecule-specific, isotopic fractionation occurs in the body. Our preliminary results suggest that natural Li isotope variations can shed light on its regulation in the body, being active or passive.