Effect of maternal cholestasis on the kinetics of bile acid transport across the canalicular membrane of infant rat livers.

Abstract

A reversible impairment in the ability of the liver to secrete cholephilic compounds has been reported to exist in infant rats born from mothers with surgically induced complete cholestasis during the last third of the pregnancy. Canalicular plasma membranes (CPM) were purified from livers obtained from 4 and 8 week-old offspring of healthy or cholestatic rats. Using radiolabelled glycocholic acid (GC) and a rapid filtration technique, bile acid transport by CPM vesicles in the presence of 3 mM ATP plus an ATP-regenerating system was measured at varying substrate concentrations. Kinetic parameters were calculated by nonlinear regression analysis. Similar values for the apparent affinity constant (Kt) were found in all experimental groups (approximately 350 microM). The value of the maximal velocity of the transport (Vmax) was similar for CPM obtained from control animals at 4 or 8 weeks of age (approximately 1.5 nmol/20 s/mg protein). In the offspring of cholestatic mothers the Vmax value was not different from that found in control animals as far as 4 week-old rats were concerned. However, Vmax in the 8 week-old group from cholestatic mothers was two-fold higher than that found in the rest of the experimental groups. Thus, the efficiency of transport, defined as Vmax/Kt, was very similar in all experimental groups, except in the group of 8 week-old offspring of cholestatic mothers, where this value was 60% higher. Isolated livers obtained from this group were able to secrete a tracer dose of radiolabelled GC (11.25 nmol) into bile significantly faster than isolated livers obtained from control animals of the same age (8 weeks). In sum, these results indicate that, in young infant rats (4 week-old), in which the maximal secretion rate for bile acids was reduced by maternal cholestasis during pregnancy, the kinetics of ATP-dependent bile acid transport across the canalicular membrane were not affected. By contrast, in older infant rats (8 week-old), in which the overall ability of the liver to secrete bile acids seems to be restored to normality, the efficiency of the canalicular transport system was actually enhanced. This suggests the existence of compensation at the level of the canalicular membrane transfer and thus that there is another hitherto unidentified mechanism involved in bile acid secretion.