The presence of a microsomal UDP-glucuronyl transferase for bilirubin in homozygous jaundiced gunn rats and in the crigler-najjar syndrome

Abstract

The infusion of a closely related derivative of bilirubin, its dimethyl diester (DME), into jaundiced (jj) Gunn rats were associated with biliary excretion of mono- and diglucuronides of bilirubin. In vitro incubation of DME with liver microsomes from jj rats demonstrated sequential demethylation and glucuronidation of DME. Liver microsomes from a patient with the Crigler-Najjar syndrome were unable to form glucuronides of bilirubin in vitro unless DME was used as substrate. The results suggest that the deficiency in Gunn rats and in the Crigler-Najjar syndrome may be due to a structural defect in the microsomal matrix which contains glucuronyl transferase. This interpretation envisions a microenvironment of the transferase enzyme which is either impermeable to bilirubin or induces conformational changes which interfere with glucuronidation.

Expression of a human liver cDNA encoding a UDP‐glucuronosyltransferase catalysing the glucuronidation of hyodeoxycholic acid in cell culture

“…However, it was recently demonstrated by gas chromatography/ mass spectrometry analysis that the glucuronides of hyodeoxycholic acid enzymaticaily synthesized with microsomes of human liver and kidney were exclusively conjugated at the 6~-hydroxy position [6]. The hyodeoxycholate conjugate was not alkalilabile after an overnight exposure to ammonia vapour [21], whereas bilirubin glucuronides were ammonia-lysed (not shown), suggesting that the bile acid glucuronide formed was not ester linked.…”

Supplement of liver enzyme by intestinal and kidney transplants in congenitally enzyme-deficient rat

“…Crigler-Najjar syndrome 1 type I is an autosomal recessive genetic disorder that is characterized by severe unconjugated hyperbilirubinemia caused by a deficiency of bilirubin-uridine diphosphate glucuronyltransferase (B-UDP-GT), the hepatic microsomal enzyme essential for bilirubin conjugation. 2 Liver transplantation is the only effective long-term therapy for this disease and has been tried using whole liver 3 or partial liver. 4 Gunn rat is an excellent animal model of Crigler-Najjar syndrome type I.…”

Conjugation and Excretion of Bilirubin

“…UDP-glucuronyl transferase activities in human liver toward both 2-aminophenol and bilirubin develop after birth.99 (4) Although Gunn rat livers lack UDP-glucuronyl transferase activity toward bilirubin, Gunn rats have been reported to excrete infused bilirubin dimethyl ester in bile partly converted to bilirubin mono-and d i g l u c u r~n i d e .~~ Incubation of bilirubin dimethyl ester with UDPglucuronic acid was found to result in sequential formation o f bilirubin and bilirubin glucuronides. 96 The authors interpreted this finding as indicating that bilirubin UDP-glucuronyl transferase in Gunn rat livers is normal; the defective activity may be due to a defect in the lipid membranes. Since a generalized defect in the lipid membranes could explain varying degrees of UDP-glucuronyl transferase defect with different substrates, the findings were thought to be evidence against a multiplicity of UDP-glucuronyl transferases.…”