Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme Selectivity
Propranolol, a non-selective beta-blocker medication, has been utilized in the treatment of cardiovascular diseases for several decades. Its hydroxynaphthyl metabolites have been recognized to possess varying degrees of beta-blocker activity due to the unaltered side-chain. This study achieved the s...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-11-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/28/23/7783 |
| _version_ | 1797399816897036288 |
|---|---|
| author | Fan Yang Maxi Wenzel Matthias Bureik Maria Kristina Parr |
| author_facet | Fan Yang Maxi Wenzel Matthias Bureik Maria Kristina Parr |
| author_sort | Fan Yang |
| collection | DOAJ |
| description | Propranolol, a non-selective beta-blocker medication, has been utilized in the treatment of cardiovascular diseases for several decades. Its hydroxynaphthyl metabolites have been recognized to possess varying degrees of beta-blocker activity due to the unaltered side-chain. This study achieved the successful separation and identification of diastereomeric glucuronic metabolites derived from 4-, 5-, and 7-hydroxypropranolol (4-OHP, 5-OHP, and 7-OHP) in human urine. Subsequently, reaction phenotyping of 5- and 7-hydroxypropranolol by different uridine 5’-diphospho-glucuronosyltransferases (UGTs) was carried out, with a comparison to the glucuronidation of 4-hydroxypropranolol (4-OHP). Among the 19 UGT enzymes examined, UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2A1, and UGT2A2 were found to be involved in the glucuronidation of 5-OHP. Furthermore, UGT1A6 exhibited glucuronidation activity towards 7-OHP, along with the aforementioned eight UGTs. Results obtained by glucuronidation of corresponding methoxypropranolols and MS/MS analysis of 1,2-dimethylimidazole-4-sulfonyl (DMIS) derivatives of hydroxypropranolol glucuronides suggest that both the aromatic and aliphatic hydroxy groups of the hydroxypropranolols may be glucuronidated in vitro. However, the analysis of human urine samples collected after the administration of propranolol leads us to conclude that aromatic-linked glucuronidation is the preferred pathway under physiological conditions. |
| first_indexed | 2024-03-09T01:45:36Z |
| format | Article |
| id | doaj.art-06f2fdadd48a470e993c2f4c1a4123ed |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T01:45:36Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-06f2fdadd48a470e993c2f4c1a4123ed2023-12-08T15:22:19ZengMDPI AGMolecules1420-30492023-11-012823778310.3390/molecules28237783Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme SelectivityFan Yang0Maxi Wenzel1Matthias Bureik2Maria Kristina Parr3Pharmaceutical and Medicinal Chemistry (Pharmaceutical Analyses), Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, GermanyPharmaceutical and Medicinal Chemistry (Pharmaceutical Analyses), 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, a non-selective beta-blocker medication, has been utilized in the treatment of cardiovascular diseases for several decades. Its hydroxynaphthyl metabolites have been recognized to possess varying degrees of beta-blocker activity due to the unaltered side-chain. This study achieved the successful separation and identification of diastereomeric glucuronic metabolites derived from 4-, 5-, and 7-hydroxypropranolol (4-OHP, 5-OHP, and 7-OHP) in human urine. Subsequently, reaction phenotyping of 5- and 7-hydroxypropranolol by different uridine 5’-diphospho-glucuronosyltransferases (UGTs) was carried out, with a comparison to the glucuronidation of 4-hydroxypropranolol (4-OHP). Among the 19 UGT enzymes examined, UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2A1, and UGT2A2 were found to be involved in the glucuronidation of 5-OHP. Furthermore, UGT1A6 exhibited glucuronidation activity towards 7-OHP, along with the aforementioned eight UGTs. Results obtained by glucuronidation of corresponding methoxypropranolols and MS/MS analysis of 1,2-dimethylimidazole-4-sulfonyl (DMIS) derivatives of hydroxypropranolol glucuronides suggest that both the aromatic and aliphatic hydroxy groups of the hydroxypropranolols may be glucuronidated in vitro. However, the analysis of human urine samples collected after the administration of propranolol leads us to conclude that aromatic-linked glucuronidation is the preferred pathway under physiological conditions.https://www.mdpi.com/1420-3049/28/23/7783UGTshydroxypropranololglucuronidationenzyme bagsdrug metabolismstructural investigation |
| spellingShingle | Fan Yang Maxi Wenzel Matthias Bureik Maria Kristina Parr Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme Selectivity Molecules UGTs hydroxypropranolol glucuronidation enzyme bags drug metabolism structural investigation |
| title | Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme Selectivity |
| title_full | Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme Selectivity |
| title_fullStr | Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme Selectivity |
| title_full_unstemmed | Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme Selectivity |
| title_short | Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme Selectivity |
| title_sort | glucuronidation pathways of 5 and 7 hydroxypropranolol determination of glucuronide structures and enzyme selectivity |
| topic | UGTs hydroxypropranolol glucuronidation enzyme bags drug metabolism structural investigation |
| url | https://www.mdpi.com/1420-3049/28/23/7783 |
| work_keys_str_mv | AT fanyang glucuronidationpathwaysof5and7hydroxypropranololdeterminationofglucuronidestructuresandenzymeselectivity AT maxiwenzel glucuronidationpathwaysof5and7hydroxypropranololdeterminationofglucuronidestructuresandenzymeselectivity AT matthiasbureik glucuronidationpathwaysof5and7hydroxypropranololdeterminationofglucuronidestructuresandenzymeselectivity AT mariakristinaparr glucuronidationpathwaysof5and7hydroxypropranololdeterminationofglucuronidestructuresandenzymeselectivity |