Glucuronidation of diflunisal, (-)-morphine, 4-nitrophenol, and propofol in liver microsomes of two patients with Crigler-Najjar syndrome type I.
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.
Brunelle
F M
FM
Pharmacokinetics Laboratory, School of Pharmacy, University Hospital St. Luc, Catholic University of Louvain, Brussels, Belgium.
Raoof
A A
AA
de ville de Goyet
J
J
Verbeeck
R K
RK
D000701:Analgesics, Opioid / Q000378:metabolism; D018686:Anesthetics, Intravenous / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D002675:Child, Preschool; D003414:Crigler-Najjar Syndrome / Q000201:enzymology / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004061:Diflunisal / Q000378:metabolism; D005260:Female; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009020:Morphine / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D015742:Propofol / Q000378:metabolism
D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005965:Glucuronates; D009596:Nitrophenols; D009020:Morphine; D004061:Diflunisal; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; C024836:4-nitrophenol; D015742:Propofol