N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles]
Maw, H. H., Zeng, X., Campbell, S., Taub, M. E., Teitelbaum, A. M.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
Published 2018
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
Published 2018
| Publication Date: |
2018-05-01
|
|---|---|
| Publisher: |
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
|
| Print ISSN: |
0090-9556
|
| Electronic ISSN: |
1521-009X
|
| Topics: |
Chemistry and Pharmacology
Medicine
|
| Published by: |
| _version_ | 1836398913552121856 |
|---|---|
| autor | Maw, H. H., Zeng, X., Campbell, S., Taub, M. E., Teitelbaum, A. M. |
| beschreibung | BI 187004, an 11 β -hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N -methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N -methylbenzimidazole metabolite [ N -methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N -methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O -methyltransferase (rhCOMT), histamine N -methyltransferase (rhHNMT), nicotinamide N -methyltransferase (rhNNMT), glycine N -methyltransferase (rhGNMT), and thiopurine S -methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro- α -methylbenzylamine (DCMB), an inhibitor of thiol S -methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N -methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N -methylation biotransformation and an HNMT-mediated regioselective N -methylation. |
| citation_standardnr | 6247898 |
| datenlieferant | ipn_articles |
| feed_id | 1915 |
| feed_publisher | The American Society for Pharmacology and Experimental Therapeutics (ASPET) |
| feed_publisher_url | http://www.aspet.org/ |
| insertion_date | 2018-05-01 |
| journaleissn | 1521-009X |
| journalissn | 0090-9556 |
| publikationsjahr_anzeige | 2018 |
| publikationsjahr_facette | 2018 |
| publikationsjahr_intervall | 7984:2015-2019 |
| publikationsjahr_sort | 2018 |
| publisher | The American Society for Pharmacology and Experimental Therapeutics (ASPET) |
| quelle | Drug Metabolism and Disposition |
| relation | http://dmd.aspetjournals.org/cgi/content/short/46/6/770?rss=1 |
| search_space | articles |
| shingle_author_1 | Maw, H. H., Zeng, X., Campbell, S., Taub, M. E., Teitelbaum, A. M. |
| shingle_author_2 | Maw, H. H., Zeng, X., Campbell, S., Taub, M. E., Teitelbaum, A. M. |
| shingle_author_3 | Maw, H. H., Zeng, X., Campbell, S., Taub, M. E., Teitelbaum, A. M. |
| shingle_author_4 | Maw, H. H., Zeng, X., Campbell, S., Taub, M. E., Teitelbaum, A. M. |
| shingle_catch_all_1 | N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles] BI 187004, an 11 β -hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N -methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N -methylbenzimidazole metabolite [ N -methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N -methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O -methyltransferase (rhCOMT), histamine N -methyltransferase (rhHNMT), nicotinamide N -methyltransferase (rhNNMT), glycine N -methyltransferase (rhGNMT), and thiopurine S -methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro- α -methylbenzylamine (DCMB), an inhibitor of thiol S -methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N -methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N -methylation biotransformation and an HNMT-mediated regioselective N -methylation. Maw, H. H., Zeng, X., Campbell, S., Taub, M. E., Teitelbaum, A. M. The American Society for Pharmacology and Experimental Therapeutics (ASPET) 0090-9556 00909556 1521-009X 1521009X |
| shingle_catch_all_2 | N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles] BI 187004, an 11 β -hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N -methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N -methylbenzimidazole metabolite [ N -methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N -methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O -methyltransferase (rhCOMT), histamine N -methyltransferase (rhHNMT), nicotinamide N -methyltransferase (rhNNMT), glycine N -methyltransferase (rhGNMT), and thiopurine S -methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro- α -methylbenzylamine (DCMB), an inhibitor of thiol S -methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N -methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N -methylation biotransformation and an HNMT-mediated regioselective N -methylation. Maw, H. H., Zeng, X., Campbell, S., Taub, M. E., Teitelbaum, A. M. The American Society for Pharmacology and Experimental Therapeutics (ASPET) 0090-9556 00909556 1521-009X 1521009X |
| shingle_catch_all_3 | N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles] BI 187004, an 11 β -hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N -methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N -methylbenzimidazole metabolite [ N -methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N -methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O -methyltransferase (rhCOMT), histamine N -methyltransferase (rhHNMT), nicotinamide N -methyltransferase (rhNNMT), glycine N -methyltransferase (rhGNMT), and thiopurine S -methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro- α -methylbenzylamine (DCMB), an inhibitor of thiol S -methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N -methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N -methylation biotransformation and an HNMT-mediated regioselective N -methylation. Maw, H. H., Zeng, X., Campbell, S., Taub, M. E., Teitelbaum, A. M. The American Society for Pharmacology and Experimental Therapeutics (ASPET) 0090-9556 00909556 1521-009X 1521009X |
| shingle_catch_all_4 | N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles] BI 187004, an 11 β -hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N -methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N -methylbenzimidazole metabolite [ N -methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N -methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O -methyltransferase (rhCOMT), histamine N -methyltransferase (rhHNMT), nicotinamide N -methyltransferase (rhNNMT), glycine N -methyltransferase (rhGNMT), and thiopurine S -methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro- α -methylbenzylamine (DCMB), an inhibitor of thiol S -methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N -methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N -methylation biotransformation and an HNMT-mediated regioselective N -methylation. Maw, H. H., Zeng, X., Campbell, S., Taub, M. E., Teitelbaum, A. M. The American Society for Pharmacology and Experimental Therapeutics (ASPET) 0090-9556 00909556 1521-009X 1521009X |
| shingle_title_1 | N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles] |
| shingle_title_2 | N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles] |
| shingle_title_3 | N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles] |
| shingle_title_4 | N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles] |
| timestamp | 2025-06-30T23:34:38.474Z |
| titel | N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles] |
| titel_suche | N-Methylation of BI 187004 by Thiol S-Methyltransferase [Articles] |
| topic | V WW-YZ |
| uid | ipn_articles_6247898 |