KINETIC-PROPERTIES OF BILIRUBIN UDP-GLUCURONYLTRANSFERASE IN SQUIRREL-MONKEYS EXHIBITING FASTING HYPERBILIRUBINEMIA

1. Bolivian squirrel monkeys (BoSM), unlike Brazilian squirrel monkeys (BrSM), exhibit a marked fasting hyperbilirubinemia (FH) and serve as animal models for Gilbert's syndrome type 1. 2. Compared to BrSM, BoSM possess a higher apparent (UDPGA)K(m) (0.51 vs 0.29 mM) and lower V(m) (0.36 vs 0.48 nmol BR conjugated/min per mg microsomal protein) for hepatic bilirubin (BR) UDP-glucuronyltransferase (BR UDPG-T). 3. Lineweaver-Burk plots are linear and obey Michaelis-Menten kinetics when UDP-acetylglucosamine is used as activator and UDPGA substrate concentrations are within the physiologic range present in the liver during the fed and fasted state (0.10-0.71 mM); above these concentrations, there is a discontinuity of kinetic plots as noted in other species. 4. There is no effect of fasting on the K(m) of BR conjugation (i.e. sum of mono- and diglucuronides) in either monkey; however, fasting is associated with lower V(m) values (15-20%) in each subspecies. 5. By calculating the potential BR flux (nmol BR conjugated/min per kg) using known hepatic UDPGA concentrations, liver weights and in vitro K(m) and V(m), a markedly lower BR flux is observed in BoSM (58.4 nmol/min per kg) than in BrSM (91.6 nmol/min per kg). 6. Significantly higher apparent (UDPGA)K(m) and lower V(m) of BR UDPG-T for conjugation of BR to BR monoglucuronide appears responsible in part for the four- to five-fold elevations in unconjugated BR in the liver and plasma in the fasted BoSM.