Maximal Biliary Secretion of Bilirubin in the Anaesthetized Rat: Dependence on UDP-glucuronosyltransferase Activity

1. Hepatic bilirubin UDP-glucuronosyl transferase activity in heterozygous Gunn rats (Jj) was only two-thirds of that in the parent Wistar rats (JJ). The former excreted only 30% of their bilirubin conjugates into bile as diglucuronide in contrast to 48% in the Wistar rats. As similar changes have been observed in Gilbert's syndrome, heterozygous Gunn rats can be used as a model for this disorder. 2. Treatment for 2 weeks with phenobarbitone or glutethimide produced a 2.6- and a 1.3-fold increase in hepatic glucuronosyltransferase activity in Wistar and heterozygous Gunn rats respectively. Bilirubin apparent maximal biliary secretory capacity (Tm) was enhanced in all animals pretreated with the enzyme inducing agents. A relationship was found between the transferase activity and the Tm value. At low transferase activities (Jj rats) a small increase in enzyme activity was accompanied by a marked enhancement of the Tm; at higher enzyme activities (Wistar rats) the increase in Tm. was less pronounced. These data suggest that the maximal biliary secretion of bilirubin is dependent on conjugation capacity, and that the currently used assay of the digitonin-activiated glucuronosyltransferase yields physiologically meaningful data. 3. In general, bilirubin diglucuronide excretion in bile increased in parallel with higher hepatic glucuronosyltransferase activities, as previously documented in man. However, this relationship was not present in glutethimide-pretreated animals. A high bilirubin load decreased the diglucuronide output in heterozygous Gunn rats. These observations demonstrate that the ratio of mono- to di-glucuronide in bile is mainly but not solely determined by the transferase activity.