We studied a possible acinar heterogeneity in the transport of organic cations, using rhodamine B as model compound. Employing perfusions of isolated rat livers in the ante-and retrograde mode and quantitative fluorescence microscopy, Zones 1 and 3 were shown to be equally efficient in taking up rhodamine B. Ten minutes after injection in an antegrade perfusion, 95% of the dose was localized in the portal half of the acinus. Fifty minutes later, however, the amount, of rhodamine B in Zone 1 had been reduced to 23%; 30 and 31% were in Zones 2 and 3, respectively, and the medium concentration was doubled. Thus, unchanged rhodamine B appeared to be transported downstream within the liver, either via the medium or directly from cell to cell, finally resulting in a relatively higher rhodamine B concentration in Zone 3. To obtain additional data, we designed a perfusion setup in which the zones could be studied separately. In both zones, the amount excreted into the medium was about 30 times the amount excreted into bile. Intracellular sequestration of rhodamine B and the rate constant for sinusoidal secretion were higher in Zone 3, while the sinusoidal uptake rates were equal; biliary excretion was higher in Zone 1.
Acinar distribution changed with time because rhodamine B, primarily accumulated in Zone 1, was secreted into the sinusoids and taken up again by downstream cells. The finally higher rhodamine B concentration in Zone 3 was caused by a zonal heterogeneity in intracellular sequestration and sinusoidal secretion of rhodamine B.
The hepatic acinus, the niicrovascular unit of the liver, consists of a heterogeneous hepatocyte population. Sinusoidal blood flows from the terminal portal venule towards the terminal hepatic venule, causing different microenvironments around the periportal (Zone 1) and the perivenous (Zone 3) cells. A heterogeneity is observed not only in structure and metabolic functions (1, 2), but also in transport functions ( 3 -5 ) . In sinusoidal blood, a Zone 1-to-Zone 3 concentration gradient of substances taken up efficiently by the liver was reported (5,6).
Provided that the hepatocytes along the acinus have equal transport characteristics, a similar concentration gradient would be anticipated inside the cells. Jones et al. ( 7) demonstrated such a gradient for the bile acid