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Research ArticleArticle

Prominent but Reverse Stereoselectivity in Propranolol Glucuronidation by Human UDP-Glucuronosyltransferases 1A9 and 1A10

Taina Sten, Saana Qvisen, Päivi Uutela, Leena Luukkanen, Risto Kostiainen and Moshe Finel
Drug Metabolism and Disposition September 2006, 34 (9) 1488-1494; DOI: https://doi.org/10.1124/dmd.106.010371
Taina Sten
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Saana Qvisen
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Päivi Uutela
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Leena Luukkanen
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Risto Kostiainen
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Moshe Finel
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Abstract

Propranolol is a nonselective β-adrenergic blocker used as a racemic mixture in the treatment of hypertension, cardiac arrhythmias, and angina pectoris. For study of the stereoselective glucuronidation of this drug, the two propranolol glucuronide diastereomers were biosynthesized, purified, and characterized. A screen of 15 recombinant human UDP-glucuronosyltransferases (UGTs) indicated that only a few isoforms catalyze propranolol glucuronidation. Analysis of UGT2B4 and UGT2B7 revealed no significant stereoselectivity, but these two enzymes differed in glucuronidation kinetics. The glucuronidation kinetics of R-propranolol by UGT2B4 exhibited a sigmoid curve, whereas the glucuronidation of the same substrate by UGT2B7 was inhibited by substrate concentrations above 1 mM. Among the UGTs of subfamily 1A, UGT1A9 and UGT1A10 displayed high and, surprisingly, opposite stereoselectivity in the glucuronidation of propranolol enantiomers. UGT1A9 glucuronidated S-propranolol much faster than R-propranolol, whereas UGT1A10 exhibited the opposite enantiomer preference. Nonetheless, the Km values for the two enantiomers, both for UGT1A9 and for UGT1A10, were in the same range, suggesting similar affinities for the two enantiomers. Unlike UGT1A9, the expression of UGT1A10 is extrahepatic. Hence, the reverse stereoselectivity of these two UGTs may signify specific differences in the glucuronidation of propranolol enantiomers between intestine and liver microsomes. Subsequent experiments confirmed this hypothesis: human liver microsomes glucuronidated S-propranolol faster than R-propranolol, whereas human intestine microsomes glucuronidated S-propranolol faster. These findings suggest a contribution of intestinal UGTs to drug metabolism, at least for UGT1A10 substrates.

Footnotes

  • This study was supported by the Academy of Finland (to M.F., project 207535) and by the Emil Aaltonen Foundation (to T.S.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.010371.

  • ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; HIM, human intestine microsomes; HLM, human liver microsomes; HPLC, high-performance liquid chromatography; LC-MS, liquid chromatography-mass spectrometry; UDP-GA, UDP-glucuronic acid; R-pg, R-propranolol glucuronide; S-pg, S-propranolol glucuronide.

    • Received March 31, 2006.
    • Accepted June 1, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (9)
Drug Metabolism and Disposition
Vol. 34, Issue 9
1 Sep 2006
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Research ArticleArticle

Prominent but Reverse Stereoselectivity in Propranolol Glucuronidation by Human UDP-Glucuronosyltransferases 1A9 and 1A10

Taina Sten, Saana Qvisen, Päivi Uutela, Leena Luukkanen, Risto Kostiainen and Moshe Finel
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1488-1494; DOI: https://doi.org/10.1124/dmd.106.010371

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Research ArticleArticle

Prominent but Reverse Stereoselectivity in Propranolol Glucuronidation by Human UDP-Glucuronosyltransferases 1A9 and 1A10

Taina Sten, Saana Qvisen, Päivi Uutela, Leena Luukkanen, Risto Kostiainen and Moshe Finel
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1488-1494; DOI: https://doi.org/10.1124/dmd.106.010371
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