Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families
Propranolol is a competitive non-selective beta-receptor antagonist that is available on the market as a racemic mixture. In the present study, glucuronidation of propranolol and its equipotent phase I metabolite 4-hydroxypropranolol by all 19 members of the human UGT1 and UGT2 families was monitore...
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MDPI AG
2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/13/7476 |
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| author | Fan Yang Sijie Liu Gerhard Wolber Matthias Bureik Maria Kristina Parr |
| author_facet | Fan Yang Sijie Liu Gerhard Wolber Matthias Bureik Maria Kristina Parr |
| author_sort | Fan Yang |
| collection | DOAJ |
| description | Propranolol is a competitive non-selective beta-receptor antagonist that is available on the market as a racemic mixture. In the present study, glucuronidation of propranolol and its equipotent phase I metabolite 4-hydroxypropranolol by all 19 members of the human UGT1 and UGT2 families was monitored. UGT1A7, UGT1A9, UGT1A10 and UGT2A1 were found to glucuronidate propranolol, with UGT1A7, UGT1A9 and UGT2A1 mainly acting on (<i>S</i>)-propranolol, while UGT1A10 displays the opposite stereoselectivity. UGT1A7, UGT1A9 and UGT2A1 were also found to glucuronidate 4-hydroxypropranolol. In contrast to propranolol, 4-hydroxypropranolol was found to be glucuronidated by UGT1A8 but not by UGT1A10. Additional biotransformations with 4-methoxypropanolol demonstrated different regioselectivities of these UGTs with respect to the aliphatic and aromatic hydroxy groups of the substrate. Modeling and molecular docking studies were performed to explain the stereoselective glucuronidation of the substrates under study. |
| first_indexed | 2024-03-09T04:06:11Z |
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| id | doaj.art-0299c7d29e7b4494b2e19ab6b8734771 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T04:06:11Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0299c7d29e7b4494b2e19ab6b87347712023-12-03T14:05:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012313747610.3390/ijms23137476Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 FamiliesFan Yang0Sijie Liu1Gerhard Wolber2Matthias Bureik3Maria Kristina Parr4Pharmaceutical and Medicinal Chemistry (Pharmaceutical Analyses), Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, GermanyPharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, GermanyPharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, GermanySchool of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, ChinaPharmaceutical and Medicinal Chemistry (Pharmaceutical Analyses), Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, GermanyPropranolol is a competitive non-selective beta-receptor antagonist that is available on the market as a racemic mixture. In the present study, glucuronidation of propranolol and its equipotent phase I metabolite 4-hydroxypropranolol by all 19 members of the human UGT1 and UGT2 families was monitored. UGT1A7, UGT1A9, UGT1A10 and UGT2A1 were found to glucuronidate propranolol, with UGT1A7, UGT1A9 and UGT2A1 mainly acting on (<i>S</i>)-propranolol, while UGT1A10 displays the opposite stereoselectivity. UGT1A7, UGT1A9 and UGT2A1 were also found to glucuronidate 4-hydroxypropranolol. In contrast to propranolol, 4-hydroxypropranolol was found to be glucuronidated by UGT1A8 but not by UGT1A10. Additional biotransformations with 4-methoxypropanolol demonstrated different regioselectivities of these UGTs with respect to the aliphatic and aromatic hydroxy groups of the substrate. Modeling and molecular docking studies were performed to explain the stereoselective glucuronidation of the substrates under study.https://www.mdpi.com/1422-0067/23/13/7476UGTspropranolol glucuronide4-hydroxypropranolol glucuronidein vitro metabolismstereoselectivityaromatic and aliphatic-linked glucuronidation |
| spellingShingle | Fan Yang Sijie Liu Gerhard Wolber Matthias Bureik Maria Kristina Parr Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families International Journal of Molecular Sciences UGTs propranolol glucuronide 4-hydroxypropranolol glucuronide in vitro metabolism stereoselectivity aromatic and aliphatic-linked glucuronidation |
| title | Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families |
| title_full | Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families |
| title_fullStr | Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families |
| title_full_unstemmed | Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families |
| title_short | Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families |
| title_sort | complete reaction phenotyping of propranolol and 4 hydroxypropranolol with the 19 enzymes of the human ugt1 and ugt2 families |
| topic | UGTs propranolol glucuronide 4-hydroxypropranolol glucuronide in vitro metabolism stereoselectivity aromatic and aliphatic-linked glucuronidation |
| url | https://www.mdpi.com/1422-0067/23/13/7476 |
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