The infusion of a closely related derivative of bilirubin, its dimethyl diester (DME), into jaundiced (jj) Gunn rats was associated with biliary excretion of mono-and diglucuronides of bilirubin. In uitro 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.
The homozygous Gunn rat ( j j , -/-) has lifelong unconjugated hyperbilirubinemia and cannot conjugate bilirubin to form an ester glucuronide in uiuo or when hepatic microsomes are assayed in uztro (1-3). Their microsomes also exhibit partial glucuronidation deficiencies for other aglycone substrates (4). The defect in jj animals has an autosomal recessive pattern of inheritance and phenotypically resembles the autosomal recessive deficiency in man, Type 1 familial nonhemolytic icterus (Crigler-Najjar syndrome) (5). Patients with this disorder also lack hepatic microsomal glucuronyl transferase activity for the conjugation of bilirubin and usually succumb to bilirubin encephalopathy during the early weeks of life. As with the heterozygous ( j J , -/+) Gunn rat, parents and heterozygous siblings of Crigler-Najjar patients are not jaundiced but manifest a deficiency in the excretion of menthol, salicylate, and steroids as ether glucuronides (6, 7). The most common interpretation of the basic defect in these two disorders is a deficiency in