Stereoselective glucuronidation of propranolol in human and cynomolgus monkey liver microsomes: Role of human hepatic UDP-glucuronosyltransferase isoforms, UGT1A9, UGT2B4 and UGT2B7

Nobumitsu Hanioka, Keiko Hayashi, Takeshi Shimizudani, Kenjiro Nagaoka, Akiko Koeda, Shinsaku Naito, Shizuo Narimatsu

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The stereoselective glucuronidation of propranolol (PL) in human and cynomolgus monkey liver microsomes, and the roles of human hepatic UDP-glucuronosyltransferase (UGT) isofoms involved in the enantiomeric glucuronidation of PL using recombinant UGT enzymes were investigated. In Michaelis-Menten plots, R- and S-PL glucuronidation by human liver microsomes showed sigmoidal kinetics whereas the kinetics of enantiomeric PL glucuronidation by cynomolgus monkey liver microsomes was monophasic. The K m, Vmax and CLint values of cynomolgus monkey liver microsomes were generally higher than the S50, Vmax and CLmax values of human liver microsomes in R- and S-PL glucuronidation. The glucuronidation of R- and S-PL was catalyzed by at least 3 UGT isoforms: UGT1A9, UGT2B4 and UGT2B7. Michaelis-Menten plots for R- and S-PL glucuronidation by UGT1A9 were monophasic, whereas the kinetics of UGT2B7 showed sigmoidal curves. Enantiomeric R-PL glucuronidation by UGT2B4 showed sigmoidal kinetics, whereas S-PL glucuronidation displayed monophasic kinetics. UGT1A9 showed remarkable stereoselectivity in Vmax and CLint values of R-PL <S-PL. These findings demonstrate that the profiles of enantiomeric PL glucuronidation in human and cynomolgus monkey liver microsomes are largely different and suggest that the human hepatic UGT isofoms UGT1A9, UGT2B4 and UGT2B7 play distinctive roles in enantiomeric PL glucuronidation.

Original languageEnglish
Pages (from-to)293-303
Number of pages11
JournalPharmacology
Volume82
Issue number4
DOIs
Publication statusPublished - Nov 2008

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Macaca fascicularis
Liver Microsomes
Propranolol
Protein Isoforms
Liver
Glucuronosyltransferase
human UGT2B7 protein
UDP-glucuronosyltransferase 1A9

Keywords

  • Cynomolgus monkey liver microsomes
  • Human liver microsomes
  • Propranolol
  • Stereoselective glucuronidation
  • UDP-glucuronosyltransferase

ASJC Scopus subject areas

  • Pharmacology

Cite this

Stereoselective glucuronidation of propranolol in human and cynomolgus monkey liver microsomes : Role of human hepatic UDP-glucuronosyltransferase isoforms, UGT1A9, UGT2B4 and UGT2B7. / Hanioka, Nobumitsu; Hayashi, Keiko; Shimizudani, Takeshi; Nagaoka, Kenjiro; Koeda, Akiko; Naito, Shinsaku; Narimatsu, Shizuo.

In: Pharmacology, Vol. 82, No. 4, 11.2008, p. 293-303.

Research output: Contribution to journalArticle

Hanioka, Nobumitsu ; Hayashi, Keiko ; Shimizudani, Takeshi ; Nagaoka, Kenjiro ; Koeda, Akiko ; Naito, Shinsaku ; Narimatsu, Shizuo. / Stereoselective glucuronidation of propranolol in human and cynomolgus monkey liver microsomes : Role of human hepatic UDP-glucuronosyltransferase isoforms, UGT1A9, UGT2B4 and UGT2B7. In: Pharmacology. 2008 ; Vol. 82, No. 4. pp. 293-303.
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abstract = "The stereoselective glucuronidation of propranolol (PL) in human and cynomolgus monkey liver microsomes, and the roles of human hepatic UDP-glucuronosyltransferase (UGT) isofoms involved in the enantiomeric glucuronidation of PL using recombinant UGT enzymes were investigated. In Michaelis-Menten plots, R- and S-PL glucuronidation by human liver microsomes showed sigmoidal kinetics whereas the kinetics of enantiomeric PL glucuronidation by cynomolgus monkey liver microsomes was monophasic. The K m, Vmax and CLint values of cynomolgus monkey liver microsomes were generally higher than the S50, Vmax and CLmax values of human liver microsomes in R- and S-PL glucuronidation. The glucuronidation of R- and S-PL was catalyzed by at least 3 UGT isoforms: UGT1A9, UGT2B4 and UGT2B7. Michaelis-Menten plots for R- and S-PL glucuronidation by UGT1A9 were monophasic, whereas the kinetics of UGT2B7 showed sigmoidal curves. Enantiomeric R-PL glucuronidation by UGT2B4 showed sigmoidal kinetics, whereas S-PL glucuronidation displayed monophasic kinetics. UGT1A9 showed remarkable stereoselectivity in Vmax and CLint values of R-PL <S-PL. These findings demonstrate that the profiles of enantiomeric PL glucuronidation in human and cynomolgus monkey liver microsomes are largely different and suggest that the human hepatic UGT isofoms UGT1A9, UGT2B4 and UGT2B7 play distinctive roles in enantiomeric PL glucuronidation.",
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