Heterogeneity of rat hepatocytes in transport and hepatic binding of asialo-alkaline phosphatase studied after induction of selective acinar damage by N-hydroxy-2-acetylaminofluorene and carbon tetrachloride

Abstract

In order to investigate rat hepatocyte heterogeneity in asialoglycoprotein transport, rats were pretreated with N-hydroxy-2-acetylaminofluorene (N-OH-AAF, 90 smmol/kg, i.v.) to damage zone 1 hepatocytes, or with carbon tetrachloride (CCl 4, 2.1 mmole/kg, p.o.) to damage zone 3 hepatocytes. Twenty-four hours after pretreatment, the asialoglycoprotein dog intestinal alkaline phosphatase (As-ALPase) was injected and plasma disappearance and biliary excretion were measured. In addition, the acinar distribution of the hepatic binding of As-ALPase 10 min after injection in vivo, or after incubation of fixed liver sections with As-ALPase in vitro, was determined by enzyme histochemistry. In control rats, a rapid biexponential plasma disappearance was observed and 6.4 ± 1.5% of the dose was excreted into bile after 60 min. Hepatocyte binding occurred predominantly in zone 3, both after administration in vivo and after incubation with liver sections in vitro. In rats with zone 1 liver damage, both the half-lives of the first and of the second phase were strongly increased, but biliary excretion did not change significantly. Both in vivo and in vitro the relatively weak binding of As-ALPase in zone 1 of the liver was abolished, whereas binding to zone 3 cells was normal or only slightly decreased. After CCl 4-pretreatment histochemically detectable binding to zone 3 cells was completely abolished, leaving only the relatively weak binding in zone 1. Unexpectedly, a normal plasma disappearance and biliary excretion rate were found in these rats. The discrepancy between the pharmacokinetic results, which point to a predominant involvement of zone 1 cells in As-ALPase transport, and the enzyme histochemical studies, which show preferential binding of As-ALPase in zone 3, is discussed.