![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 299, Issue 3, 998-1006, December 2001
Molecular Pharmacogenetics (M.H.C., S.X.D.) and Clinical
Pharmacology (L.L.v.M., D.J.G.) Laboratories, Department of
Pharmacology and Experimental Therapeutics, Tufts University School of
Medicine, Boston, Massachusetts; Gentest (C.J.P.), Woburn,
Massachusetts; and Department of Clinical Pharmacology (J.O.M.,
P.I.M.), Flinders University School of Medicine, Bedford Park, South
Australia
Interindividual variability in acetaminophen (APAP)
glucuronidation may contribute to differences in susceptibility to APAP intoxication in humans. The purpose of this study was to identify the
relevant UDP-glucuronosyltransferase (UGT) isoforms mediating APAP-UGT
activity in human liver microsomes (HLMs). APAP-UGT activities and
enzyme kinetics were determined using HLMs from 56 donors and nine
recombinant human UGTs. Activities mediated by UGT1A1, UGT1A4, UGT1A9,
and UGT2B7, and relative UGT1A6 protein content were quantified using
20 livers. More than 15-fold variation in liver microsomal APAP-UGT
activities was observed with a distribution skewed toward lower
activities. Although most UGTs could glucuronidate APAP, UGT1A1,
UGT1A6, and UGT1A9 were most active. UGT1A6 was a relatively
high-affinity (Km = 2.2 mM),
low-capacity enzyme; UGT1A1 was intermediate in affinity
(Km = 9.4 mM) and capacity; and UGT1A9
was a low-affinity (Km = 21 mM),
high-capacity enzyme. Km values were similar
to UGT1A1 in high- and intermediate-activity HLMs (6-10 mM) and UGT1A9
in low-activity HLMs (10-55 mM). APAP-UGT activities correlated best
with propofol-UGT (r = 0.85; UGT1A9) and
bilirubin-UGT (r = 0.66; UGT1A1) activities, but
poorly with UGT1A6 protein (r = 0.30). A kinetic
model was constructed from these data that identified UGT1A9 as the
predominant APAP-UGT (>55% total activity) in HLMs over a clinically
relevant APAP concentration range (50 µM-5 mM). UGT1A1 was also
predicted to contribute substantially at toxic concentrations (>1 mM;
>28% activity), whereas UGT1A6 was most active at relatively low
concentrations (<50 µM; >29% activity).
This article has been cited by other articles:
|
|
 |
|
  P. J. Murphy The Development of Drug Metabolism Research as Expressed in the Publications of ASPET: Part 3, 1984-2008 Drug Metab. Dispos., October 1, 2008; 36(10): 1977 - 1982. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-X. Liu, Y. Liu, J.-W. Zhang, W. Li, H.-T. Liu, and L. Yang UDP-Glucuronosyltransferase 1A6 Is the Major Isozyme Responsible for Protocatechuic Aldehyde Glucuronidation in Human Liver Microsomes Drug Metab. Dispos., August 1, 2008; 36(8): 1562 - 1569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. P. Volak, S. Ghirmai, J. R. Cashman, and M. H. Court Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine Is a Relatively Selective CYP3A4 Inhibitor Drug Metab. Dispos., August 1, 2008; 36(8): 1594 - 1605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Oesterheld, K. Cozza, and N. B. Sandson Oral Contraceptives Psychosomatics, April 1, 2008; 49(2): 168 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ramirez, W. Liu, S. Mirkov, A. A. Desai, P. Chen, S. Das, F. Innocenti, and M. J. Ratain Lack of Association between Common Polymorphisms in UGT1A9 and Gene Expression and Activity Drug Metab. Dispos., December 1, 2007; 35(12): 2149 - 2153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Zhang, D. Zhang, D. Cui, J. Gambardella, L. Ma, A. Barros, L. Wang, Y. Fu, S. Rahematpura, J. Nielsen, et al. Characterization of the UDP Glucuronosyltransferase Activity of Human Liver Microsomes Genotyped for the UGT1A1*28 Polymorphism Drug Metab. Dispos., December 1, 2007; 35(12): 2270 - 2280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wong, V. Tong, K. W. Riggs, D. W. Rurak, F. S. Abbott, and S. Kumar Kinetics of Valproic Acid Glucuronidation: Evidence for in Vivo Autoactivation Drug Metab. Dispos., August 1, 2007; 35(8): 1380 - 1386. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. J. Martin, R. J. Lewis, M. A. Bernstein, I. G. Beattie, C. A. Martin, R. J. Riley, and B. Springthorpe Which Hydroxy? Evidence for Species Differences in the Regioselectivity of Glucuronidation in Rat, Dog, and Human in Vitro Systems and Dog in Vivo Drug Metab. Dispos., September 1, 2006; 34(9): 1502 - 1507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Kostrubsky, J. F. Sinclair, S. C. Strom, S. Wood, E. Urda, D. B. Stolz, Y. H. Wen, S. Kulkarni, and A. Mutlib Phenobarbital and Phenytoin Increased Acetaminophen Hepatotoxicity Due to Inhibition of UDP-Glucuronosyltransferases in Cultured Human Hepatocytes Toxicol. Sci., September 1, 2005; 87(1): 146 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Luukkanen, J. Taskinen, M. Kurkela, R. Kostiainen, J. Hirvonen, and M. Finel KINETIC CHARACTERIZATION OF THE 1A SUBFAMILY OF RECOMBINANT HUMAN UDP-GLUCURONOSYLTRANSFERASES Drug Metab. Dispos., July 1, 2005; 33(7): 1017 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Krishnaswamy, Q. Hao, A. Al-Rohaimi, L. M. Hesse, L. L. von Moltke, D. J. Greenblatt, and M. H. Court UDP Glucuronosyltransferase (UGT) 1A6 Pharmacogenetics: II. Functional Impact of the Three Most Common Nonsynonymous UGT1A6 Polymorphisms (S7A, T181A, and R184S) J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1340 - 1346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Krishnaswamy, Q. Hao, A. Al-Rohaimi, L. M. Hesse, L. L. von Moltke, D. J. Greenblatt, and M. H. Court UDP Glucuronosyltransferase (UGT) 1A6 Pharmacogenetics: I. Identification of Polymorphisms in the 5'-Regulatory and Exon 1 Regions, and Association with Human Liver UGT1A6 Gene Expression and Glucuronidation J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1331 - 1339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Williams, R. Hyland, B. C. Jones, D. A. Smith, S. Hurst, T. C. Goosen, V. Peterkin, J. R. Koup, and S. E. Ball DRUG-DRUG INTERACTIONS FOR UDP-GLUCURONOSYLTRANSFERASE SUBSTRATES: A PHARMACOKINETIC EXPLANATION FOR TYPICALLY OBSERVED LOW EXPOSURE (AUCI/AUC) RATIOS Drug Metab. Dispos., November 1, 2004; 32(11): 1201 - 1208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-Q. Wang, C. N. Falany, and M. O. James TRICLOSAN AS A SUBSTRATE AND INHIBITOR OF 3'-PHOSPHOADENOSINE 5'-PHOSPHOSULFATE-SULFOTRANSFERASE AND UDP-GLUCURONOSYL TRANSFERASE IN HUMAN LIVER FRACTIONS Drug Metab. Dispos., October 1, 2004; 32(10): 1162 - 1169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Wells, P. I. Mackenzie, J. Roy Chowdhury, C. Guillemette, P. A. Gregory, Y. Ishii, A. J. Hansen, F. K. Kessler, P. M. Kim, N. Roy Chowdhury, et al. GLUCURONIDATION AND THE UDP-GLUCURONOSYLTRANSFERASES IN HEALTH AND DISEASE Drug Metab. Dispos., March 1, 2004; 32(3): 281 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gardner-Stephen, J.-M. Heydel, A. Goyal, Y. Lu, W. Xie, T. Lindblom, P. Mackenzie, and A. Radominska-Pandya HUMAN PXR VARIANTS AND THEIR DIFFERENTIAL EFFECTS ON THE REGULATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE GENE EXPRESSION Drug Metab. Dispos., March 1, 2004; 32(3): 340 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. K. Basu, M. Ciotti, M. S. Hwang, L. Kole, P. S. Mitra, J. W. Cho, and I. S. Owens Differential and Special Properties of the Major Human UGT1-encoded Gastrointestinal UDP-glucuronosyltransferases Enhance Potential to Control Chemical Uptake J. Biol. Chem., January 9, 2004; 279(2): 1429 - 1441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jinno, M. Saeki, Y. Saito, T. Tanaka-Kagawa, N. Hanioka, K. Sai, N. Kaniwa, M. Ando, K. Shirao, H. Minami, et al. Functional Characterization of Human UDP-Glucuronosyltransferase 1A9 Variant, D256N, Found in Japanese Cancer Patients J. Pharmacol. Exp. Ther., August 1, 2003; 306(2): 688 - 693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Soars, B. J. Ring, and S. A. Wrighton THE EFFECT OF INCUBATION CONDITIONS ON THE ENZYME KINETICS OF UDP-GLUCURONOSYLTRANSFERASES Drug Metab. Dispos., June 1, 2003; 31(6): 762 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. Iyer, M. N. Ho, W. M. Shinn, W. W. Bradford, M. J. Tanga, S. S. Nath, and C. E. Green Glucuronidation of 1'-Hydroxyestragole (1'-HE) by Human UDP-Glucuronosyltransferases UGT2B7 and UGT1A9 Toxicol. Sci., May 1, 2003; 73(1): 36 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Krishnaswamy, S. X. Duan, L. L. von Moltke, D. J. Greenblatt, and M. H. Court Validation of Serotonin (5-Hydroxtryptamine) as an in Vitro Substrate Probe for Human UDP-Glucuronosyltransferase (UGT) 1A6 Drug Metab. Dispos., January 1, 2003; 31(1): 133 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Ghosheh and E. M. Hawes Microsomal N-Glucuronidation of Nicotine and Cotinine: Human Hepatic Interindividual, Human Intertissue, and Interspecies Hepatic Variation Drug Metab. Dispos., December 1, 2002; 30(12): 1478 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-F. Gagne, V. Montminy, P. Belanger, K. Journault, G. Gaucher, and C. Guillemette Common Human UGT1A Polymorphisms and the Altered Metabolism of Irinotecan Active Metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38) Mol. Pharmacol., September 1, 2002; 62(3): 608 - 617. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
