Zonal distribution of the cation lucigenin in rat liver: influence of taurocholate.
The yellow fluorescent cation lucigenin (LU) was used as a model compound to study acinar heterogeneity in transport of hydrophilic cations that enter the liver by adsorptive endocytosis. Hepatic uptake was fast and saturable. The extraction was about 50% in a cyclically perfused rat liver preparation in which endogenous bile salts were replaced by the infusion of taurocholate (TC). Fluorescence microscopy on 8-microns liver sections revealed a striking distribution pattern. LU appeared to be concentrated in micro- and macrovesicular structures in the cell. At the same time, LU skipped the first cells of the acinus, zone 1 in an antegrade and zone 3 in a retrograde perfusion. A downstream localization of the dye was the result. Single-pass perfusions with TC concentrations ranging from 0 to 180 microM showed that hepatic clearance of LU negatively correlated with the TC concentration (p less than 0.005). Clearance fell from 1.99 +/- 0.06 ml/min-g of liver(mean +/- SD) without TC to 1.61 +/- 0.21 with 45 microM TC and 1.65 +/- 0.12 with 180 microM TC. Moreover, in the absence of TC we observed a homogeneous distribution of LU. TC induced in the acinus a nonfluorescent upstream area that expanded with increasing TC concentration. We concluded that TC inhibited uptake of LU; a high medium concentration of TC in zone 1 (antegrade) was accompanied by a low uptake of LU in this zone, resulting in a downstream increasing acinar gradient. Hepatic uptake and acinar distribution of certain cationic drugs in vivo may, therefore, vary with the variable input of bile salts in the portal circulation and, hence, with nutritional status and the time of day.
Braakman
I
I
Department of Pharmacology and Therapeutics, Groningen University, The Netherlands.
Verest
O
O
Pijning
T
T
Meijer
D K
DK
Groothuis
G M
GM
D000166:Acridines / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002412:Cations / Q000378:metabolism*; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013656:Taurocholic Acid / Q000378:metabolism*
D000166:Acridines; D002412:Cations; C033472:10,10'-dimethyl-9,9'-biacridinium; D013656:Taurocholic Acid