ISOFORM SELECTIVITY AND KINETICS OF MORPHINE 3- AND 6-GLUCURONIDATION BY HUMAN UDP-GLUCURONOSYLTRANSFERASES: EVIDENCE FOR ATYPICAL GLUCURONIDATION KINETICS BY UGT2B7
作者： Andrew N. Stone , Peter I. Mackenzie , Aleksandra Galetin , J. Brian Houston , John O. Miners
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摘要: Morphine elimination involves UDP-glucuronosyltransferase (UGT) catalyzed conjugation with glucuronic acid to form morphine 3- and 6-glucuronides (M3G M6G, respectively). It has been proposed that UGT2B7 is the major enzyme involved in these reactions, but there evidence suggest other isoforms also catalyze glucuronidation man. Thus, we have characterized selectivity kinetics of M3G M6G formation by recombinant human UGTs. UGT 1A1, 1A3, 1A6, 1A8, 1A9, 1A10, 2B7 all formation, only formed M6G. The UGT1A family was consistent a single Michaelis-Menten model, apparent Km values ranging from 2.6 37.4 mM. In contrast, exhibited atypical kinetics. may be described model high- low-affinity (0.42 8.3 mM for M3G, 0.97 7.4 M6G) fitting biphasic model. However, multisite an interaction between two identical binding sites negative cooperative manner provides more realistic approach modeling data. According this respective affinities (Ks) were 1.76 1.41 mM, respectively. These data used as selective probe activity, appears involve simultaneous substrate molecules, highlighting need careful analysis vitro.
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Birgit L. Coffman, Gladys R. Rios, Thomas R. Tephly, Christopher D. King, The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metabolism and Disposition. ,vol. 26, pp. 73- 77 ,(1998)
Birgit L. Coffman, Gladys R. Rios, Thomas R. Tephly, Christopher D. King, Human UGT2B7 catalyzes morphine glucuronidation. Drug Metabolism and Disposition. ,vol. 25, pp. 1- 4 ,(1997)
C.J. Jin, J.O. Miners, K.J. Lillywhite, P.I. Mackenzie, cDNA cloning and expression of two new members of the human liver UDP-glucuronosyltransferase 2B subfamily. Biochemical and Biophysical Research Communications. ,vol. 194, pp. 496- 503 ,(1993) , 10.1006/BBRC.1993.1847
J.O. Miners, K.J. Lillywhite, D.J. Birkett, In vitro evidence for the involvement of at least two forms of human liver UDP-glucuronosyltransferase in morphine 3-glucuronidation. Biochemical Pharmacology. ,vol. 37, pp. 2839- 2845 ,(1988) , 10.1016/0006-2952(88)90048-2
Peter I. Mackenzie, Ida S. Owens, Brian Burchell, K W Bock, Amos Bairoch, Alain Belanger, Sylvie Fournel Gigleux, Mitchell Green, Dean W. Hum, Takashi Iyanagi, Doron Lancet, Pierre Louisot, Jacques Magdalou, Jayanta Roy Chowdhury, Joseph K. Ritter, Thomas R. Tephly, Harry Schachter, Thomas Tephly, Keith F Tipton, Daniel W. Nebert, The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics. ,vol. 7, pp. 255- 269 ,(1997) , 10.1097/00008571-199708000-00001
Martin Beaulieu, Éric Lévesque, Dean W. Hum, Alain Bélanger, Isolation and Characterization of a Human Orphan UDP-Glucuronosyltransferase, UGT2B11 Biochemical and Biophysical Research Communications. ,vol. 248, pp. 44- 50 ,(1998) , 10.1006/BBRC.1998.8908
John O. Miners, Peter I. Mackenzie, Drug glucuronidation in humans. Pharmacology & Therapeutics. ,vol. 51, pp. 347- 369 ,(1991) , 10.1016/0163-7258(91)90065-T
Michael J Sorich, Paul A Smith, Ross A McKinnon, John O Miners, Pharmacophore and quantitative structure activity relationship modelling of UDP-glucuronosyltransferase 1A1 (UGT1A1) substrates. Pharmacogenetics. ,vol. 12, pp. 635- 645 ,(2002) , 10.1097/00008571-200211000-00008
J B Houston, K E Kenworthy, In vitro-in vivo scaling of CYP kinetic data not consistent with the classical Michaelis-Menten model. Drug Metabolism and Disposition. ,vol. 28, pp. 246- 254 ,(2000)
Anna Radominska-Pandya, Thomas R. Tephly, Ziqiang Cheng, Studies on the Substrate Specificity of Human Intestinal UDP-Glucuronosyltransferases 1A8 and 1A10 Drug Metabolism and Disposition. ,vol. 27, pp. 1165- 1170 ,(1999)