Transport pathways for therapeutic concentrations of lithium in rat liver

Although both amiloride- and phloretin-sensitive Na(+)/Li(+) exchange activities have been reported in mammalian red blood cells, it is still unclear whether or not the two are mediated by the same pathway. Also, little is known about the relative contribution of these transport mechanisms to the entry of therapeutic concentrations of Li(+) (0.2-2 mm) into cells other than erythrocytes. Here, we describe characteristics of these transport systems in rat isolated hepatocytes in suspension. Uptake of Li(+) by hepatocytes, preloaded with Na(+) and incubated in the presence of ouabain and bumetanide, comprised three components. (a) An amiloride-sensitive component, with apparent K(m) 1.2 mm Li(+), V(max) 40 mumol. (kg dry wt. min)(-1), showed increased activity at low intracellular pH. The relationship of this component to the concentration of intracellular H(+) was curvilinear suggesting a modifier role of [H(+)](i). This system persisted in Na(+)-depleted cells, although with apparent K(m) 3.8 mm. (b) A phloretin-sensitive component, with K(m) 1.2 mm, V(max) 21 mumol. (kg. min)(-1), was unaffected by pH but was inactive in Na(+)-depleted cells. Phloretin inhibited Li(+) uptake and Na(+) efflux in parallel. (c) A residual uptake increased linearly with the external Li(+) concentration and represented an increasing proportion of the total uptake. The results strongly suggest that the amiloride-sensitive and the phloretin-sensitive Li(+) uptake in rat liver are mediated by two separate pathways which can be distinguished by their sensitivity to inhibitors and intracellular [H(+)].