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OtherShort Communication

ISOFORM SELECTIVITY AND KINETICS OF MORPHINE 3- AND 6-GLUCURONIDATION BY HUMAN UDP-GLUCURONOSYLTRANSFERASES: EVIDENCE FOR ATYPICAL GLUCURONIDATION KINETICS BY UGT2B7

Andrew N. Stone, Peter I. Mackenzie, Aleksandra Galetin, J. Brian Houston and John O. Miners
Drug Metabolism and Disposition September 2003, 31 (9) 1086-1089; DOI: https://doi.org/10.1124/dmd.31.9.1086
Andrew N. Stone
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Peter I. Mackenzie
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Aleksandra Galetin
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J. Brian Houston
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John O. Miners
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Abstract

Morphine elimination involves UDP-glucuronosyltransferase (UGT) catalyzed conjugation with glucuronic acid to form morphine 3- and 6-glucuronides (M3G and M6G, respectively). It has been proposed that UGT2B7 is the major enzyme involved in these reactions, but there is evidence to suggest that other isoforms also catalyze morphine glucuronidation in man. Thus, we have characterized the selectivity and kinetics of M3G and M6G formation by recombinant human UGTs. UGT 1A1, 1A3, 1A6, 1A8, 1A9, 1A10, and 2B7 all catalyzed M3G formation, but only UGT2B7 formed M6G. The kinetics of M3G formation by the UGT1A family isoforms was consistent with a single enzyme Michaelis-Menten model, with apparent Km values ranging from 2.6 to 37.4 mM. In contrast, M3G and M6G formation by UGT2B7 exhibited atypical kinetics. The atypical kinetics may be described by a model with high- and low-affinity Km values (0.42 and 8.3 mM for M3G, and 0.97 and 7.4 mM for M6G) from fitting to a biphasic Michaelis-Menten model. However, a multisite model with an interaction between two identical binding sites in a negative cooperative manner provides a more realistic approach to modeling these data. According to this model, the respective binding affinities (Ks) for M3G and M6G were 1.76 and 1.41 mM, respectively. These data suggest that M6G formation may be used as a selective probe for UGT2B7 activity, and morphine glucuronidation by UGT2B7 appears to involve the simultaneous binding of two substrate molecules, highlighting the need for careful analysis of morphine glucuronidation kinetics in vitro.

Footnotes

  • ↵1 Abbreviations used are: UGT, UDP-glucuronosyltransferase; UDPGA, UDP-glucuronic acid; M3G, morphine 3-glucuronide; M6G, morphine 6-glucuronide; 4MU, 4-methylumbelliferone; 4MUG, 4MU-β-d-glucuronide.

  • This work was supported by a grant from the National Health and Medical Research Council of Australia. A.N.S. was the recipient of an Australian Postgraduate Award (Industry), funded by the Commonwealth of Australia Department of Employment, Education, Training and Youth Affairs in collaboration with Faulding Pharmaceuticals.

    • Received February 26, 2003.
    • Accepted May 21, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (9)
Drug Metabolism and Disposition
Vol. 31, Issue 9
1 Sep 2003
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ISOFORM SELECTIVITY AND KINETICS OF MORPHINE 3- AND 6-GLUCURONIDATION BY HUMAN UDP-GLUCURONOSYLTRANSFERASES: EVIDENCE FOR ATYPICAL GLUCURONIDATION KINETICS BY UGT2B7
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OtherShort Communication

ISOFORM SELECTIVITY AND KINETICS OF MORPHINE 3- AND 6-GLUCURONIDATION BY HUMAN UDP-GLUCURONOSYLTRANSFERASES: EVIDENCE FOR ATYPICAL GLUCURONIDATION KINETICS BY UGT2B7

Andrew N. Stone, Peter I. Mackenzie, Aleksandra Galetin, J. Brian Houston and John O. Miners
Drug Metabolism and Disposition September 1, 2003, 31 (9) 1086-1089; DOI: https://doi.org/10.1124/dmd.31.9.1086

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OtherShort Communication

ISOFORM SELECTIVITY AND KINETICS OF MORPHINE 3- AND 6-GLUCURONIDATION BY HUMAN UDP-GLUCURONOSYLTRANSFERASES: EVIDENCE FOR ATYPICAL GLUCURONIDATION KINETICS BY UGT2B7

Andrew N. Stone, Peter I. Mackenzie, Aleksandra Galetin, J. Brian Houston and John O. Miners
Drug Metabolism and Disposition September 1, 2003, 31 (9) 1086-1089; DOI: https://doi.org/10.1124/dmd.31.9.1086
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