Pre-replicative phase-related changes in bile acid-induced choleresis in the regenerating rat liver

Abstract

1. During the pre-replicative phase of the regenerating rat liver some interesting changes occur, which might selectively modify some mechanisms involved in bile formation, such as those responsible for the hypercholeretic effect of ursodeoxycholic acid. The aim of the present work was to gain information on this point. 2. Anaesthetized male Wistar rats (∼ 250 g) were used. The animals underwent two-thirds hepatectomy 1, 6 or 12 h before collection of bile samples was begun. Very early after hepatectomy (1 h) spontaneous bile flow and bile acid output were increased. Both returned to values not significantly different from those of the controls at 6 h. Bile flow increased again at the end of the pre-replicative phase. Taurocholate infusion (200 nmol min−1 g−1 calculated liver weight) induced increases in bile flow and bile acid output that were similar in both the control and hepatectomized rats, regardless of the time of the pre-replicative phase considered. 3. Cholic acid and ursodeoxycholic acid were infused (300 nmol min−1 g−1 calculated liver weight) into control and partially hepatectomized rats (at the mid-point of the pre-replicative phase, i.e. 6 h after surgical liver resection). Cholic acid-induced bile flow, bile acid and bicarbonate output expressed per g of remaining liver were similar in control and in hepatectomized rats. By contrast, ursodeoxycholic acid-induced choleresis was profoundly altered during the pre-replicative phase. As expressed per g of remaining liver, bile flow was markedly reduced (− 17%, P < 0.05), in spite of total bile acid output being greatly increased (+ 148%, P < 0.001). The reduced choleretic effect of ursodeoxycholic acid may be due to a lowered stimulation of bicarbonate secretion (− 41%, P < 0.01). 4. Factors known to reduce ursodeoxycholic acid-induced bicarbonate secretion into bile, such as decreased plasma bicarbonate concentrations and lowered total hepatic carbonic anhydrase activity, cannot account for the loss of the ability of ursodeoxycholic acid to stimulate bicarbonate secretion during the pre-replicative phase. However, the bile acid conjugation patterns were dramatically altered early after hepatectomy (6 h). In bile from the control animals the major ursodeoxycholic acid conjugation was with glycine, whereas in hepatectomized rats it was with taurine. 5. In summary, our results indicate that during the prereplicative phase of the regenerating rat liver, a loss occurs in the hypercholeretic effect of bile acids such as ursodeoxycholic acid. However, the choleretic effect of non-hypercholeretic bile acids such as cholic acid and taurocholic acid was not altered. Moreover, the existence of a relationship between the decrease in bile flow and bicarbonate output and the marked increase in the secretion of low-pKa conjugated bile acid derivatives is suggested.