ONTOGENY OF HEPATOBILIARY SECRETION - ROLE OF GLUTATHIONE

The ontogeny of hepatic synthesis and biliary secretion of glutathione was characterized and correlated with hepatic gamma glutamyl transpep tidase, bile flow rate, biliary bile acids and amino acids in Sprague- Dawley rats at 18 days of gestation and postnatally at ages 7, 14, 21, 28 and 54 days. Bile was collected by bile duct cannulation under int raperitoneal anesthesia with nembutal/ketamine. Glutathione, gamma glu tamyl transpeptidase and bile acids were analyzed enzymatically and am ino acids by high-performance liquid chromatography using established methods. Hepatic glutathione was low in the fetus, but increased to ap proximate adult levels by 7 days postnatally (2.77 mu mol/gm liver). H epatic gamma glutamyl transpeptidase activity, high in the fetus, decl ined to adult levels by day 7 (0.03 mu mol/mg protein). In contrast, s ignificant efflux of glutathione and its constituent amino acids into bile did not occur until weaning (21 days of age). During weaning, the re was a fivefold increase in the biliary glutathione and with a twofo ld increase in bile how rate. Biliary bile acids concentration remaine d constant throughout development, with only a 30% to 50% increase in its secretion rate. The data suggest that the developmentally related increase in bile flow rate was principally a result of the increase in bile acid independent flow from 1.1 mu l/(min . 100 gm body wt) in th e suckling to 4.3 mu l/(min . 100 gm body wt) in the post-weanling ani mal. Conclusions: (1) bile formation in the suckling is largely depend ent on bile acids secretion, in the absence of a significant bile acid s independent component; (2) glutathione and amino acids play a major role in promoting bile acid independent flow; and (3) the development of mechanisms for biliary glutathione secretion succeeds those of hepa tic glutathione synthesis and provides a potential model for investiga ting the ontogeny of canalicular transport processes and the role of g lutathione in bile formation.