Uptake in the liver: the nature of the process.

The methodology developed to assess the permeability of capillaries has been extended and applied to the study of the uptake of materials by the intact liver. The sinusoidal membrane has been found to be freely permeable to dissolved substances, so that the Disse spaces are functionally a simple extension of the sinusoidal plasma space. With this free access, a concentration bolus of material dissolved in plasma is found to be propagated in a delayed fashion, to behave as if it were flowing within this larger space. Within the space an exclusion phenomenon is found: the collagen and ground substance within it reduce the proportion of the space accessible to larger molecules in a graded fashion. Beyond the Disse spaces the first biological barrier for substances characteristically taken up by the liver is the cell membrane of the hepatic parenchymal cells. The uptake of materials, in general, therefore has the characteristics of a membrane carrier transport process. The phenomena distinctively associated with this process include saturation kinetics, competitive inhibition, and isotope countertransport. Beyond the membrane those substances sequestered by biochemical transformations or biliary secretion are handled by processes that also show saturation effects. The multiple indicator dilution technique has been adapted to the study of the uptake of materials at the liver cell surface. The process has been modeled and outflow profiles have been shown to consist of a throughput component (which has not entered the cells) and a returning component (which has entered the cells and returned to the plasma space to emerge at the outflow). When the process at the cell membrane is concentrative, the throughput component is emphasized by the relatively larger delay caused in the returning component by virtue of the concentratively enlarged cellular volume. When the process is nonconcentrative, the returning component emerges earlier, so that throughput and returning components are not longer directly apparent and must be separated out by carrying out model analysis of the data with a digital computer. The uptake of tracer rubidium was found to be a typically concentrative process, and that of tracer glucose a nonconcentrative process. When substrate undergoes intracellular sequestration, a new set of phenomena emerge. The sequestration reduces the magnitude of the returning component in a tracer experiment and, with this, produces a steady state gradient in lobular concentration, a profile decreasing in magnitude from the portal area to the adjacent terminal hepatic venules. The diminution in returning components has been observed both for galactose and for the group of compounds characteristically secreted in bile in high concentration. The lobular gradient for galactose has been demonstrated autoradiographically. It is evident that a powerful new set of tools has emerged...