Glucuronidation of diflunisal, (-)-morphine, 4-nitrophenol, and propofol in liver microsomes of two patients with Crigler-Najjar syndrome type I

Abstract

In vitro glucuronidation was studied in liver microsomes from two patients with Crigler-Najjar type I (CN-I) disease and compared with the activity measured in microsomes prepared from six control human livers. The UDP-glucuronosyltransferase (UGT) activity was determined toward the following substrates: 4-nitrophenol, propofol, (-)-morphine (formation of the 3-glucuronide), and diflunisal (formation of the phenolic and acyl glucuronides). Glucuronidation of 4-nitrophenol was reduced in one of the CN-I livers (CN-I No. 1) (0.9 nmol min(-1)mg(-1)) and normal in the other CN-I liver (CN-I No. 2) (3.5 nmol min(-1) mg(-l)) compared to the control livers (5.6 +/- 29 nmol min(-1) mg(-1)), mean +/- S.D.). Propofol glucuronidation was not detectable (i.e. less than 0.100 nmol min(-l) mg(-1) in the CN-I No. 1 liver and normal in the CN-I No. 2 liver (1.78 nmol min(-1) mg(-1) against 1.52 +/ 0.72 nmol min(-l) mg(-) in the control livers). The glucuronidation of (-)-morphine to the 3-glucuronide and the formation of the phenolic and acyl glucuronides of diflunisal were normal in both CN-I livers compared to the control livers. Our results show that CN-I patients are heterogeneous regarding UGT activity toward the phenolic substances 4-nitrophenol and propofol.