Inhibitory Effects of Baicalein Derived from Japanese Traditional Herbal Medicine on SN-38 Glucuronidation
Purpose: The chemotherapeutic agent irinotecan is hydrolyzed to its active form SN-38 by human carboxyesterases, but SN-38 is converted into the inactive form SN-38G by hepatic UDP-glucuronosyltransferases (UGTs). The aim of the present study was to evaluate the inhibitory effects of two b-glucuroni...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-05-01
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| Series: | Journal of Pharmacy & Pharmaceutical Sciences |
| Online Access: | https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/29783 |
| _version_ | 1797760821279850496 |
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| author | Takashi Satoh Ayaka Igarashi Misaki Tanno Koki Yamada Natsuko Takahashi-Suzuki Kazuhiro Watanabe |
| author_facet | Takashi Satoh Ayaka Igarashi Misaki Tanno Koki Yamada Natsuko Takahashi-Suzuki Kazuhiro Watanabe |
| author_sort | Takashi Satoh |
| collection | DOAJ |
| description | Purpose: The chemotherapeutic agent irinotecan is hydrolyzed to its active form SN-38 by human carboxyesterases, but SN-38 is converted into the inactive form SN-38G by hepatic UDP-glucuronosyltransferases (UGTs). The aim of the present study was to evaluate the inhibitory effects of two b-glucuronidase-treated Japanese traditional herbal medicines (kampo), Hange-Shashin-To (TJ-14) and Sairei-To (TJ-114) on SN-38 glucuronidation, and the deglycosylation of baicalin (BG) and glycyrrhizic acid (GL) derived from TJ-14 and TJ-114 to form their respective aglycones, baicalein (BA) and glycyrrhetinic acid (GA). Methods: The inhibitory effects of b-glucuronidase-treated TJ-14 and TJ-114 on SN-38 glucuronidation by human liver microsomes were examined. BA and GA, which were enzymatically converted from BG and GL present in TJ-14 and TJ-114, were examined in the same manner. Furthermore, the enzymatic activities were measured by using recombinant UGT1A1 and UGT1A9 isoforms instead of human liver microsomes. BA, GA, SN-38, and their glycosides/glucuronides were analyzed with an LC-MS system. Results: As regards the linear initial reaction rate, SN-38 glucuronidation by human liver microsomes was significantly inhibited by the addition of b-glucuronidase-untreated TJ-14 and TJ-114, but was more strongly inhibited by the addition of b-glucuronidase-treated TJ-14 and TJ-114. The results of LC-MS analysis and pharmacokinetic studies suggested that BA is the main inhibitor of SN-38 glucuronidation. In the Dixon plot, BA showed competitive inhibition of SN-38 glucuronidation, and the inhibition constant was 8.70 ± 3.24 mM. Previous reports, studies of recombinant UGT isoforms indicated that SN-38 glucuronidation was mainly catalyzed by UGT1A1. Conclusions: These findings strongly suggested that SN-38 glucuronidation is inhibited by BA. BA could act as a pharmacokinetic regulating factor associated with SN-38 glucuronidation.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page. |
| first_indexed | 2024-03-12T19:04:04Z |
| format | Article |
| id | doaj.art-3bce13e5954d450980aeb95528a3fb95 |
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| issn | 1482-1826 |
| language | English |
| last_indexed | 2024-03-12T19:04:04Z |
| publishDate | 2018-05-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj.art-3bce13e5954d450980aeb95528a3fb952023-08-02T06:23:43ZengFrontiers Media S.A.Journal of Pharmacy & Pharmaceutical Sciences1482-18262018-05-0121110.18433/jpps29783Inhibitory Effects of Baicalein Derived from Japanese Traditional Herbal Medicine on SN-38 GlucuronidationTakashi Satoh0Ayaka Igarashi1Misaki Tanno2Koki Yamada3Natsuko Takahashi-Suzuki4Kazuhiro Watanabe5Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University of Science.Department of Pharmaceutics, Hokkaido Pharmaceutical University School of Pharmacy. Department of Pharmacy, NTT East Japan Sapporo Hospital.Department of Pharmaceutics, Hokkaido Pharmaceutical University School of Pharmacy. Department of Pharmacy, Tomakomai Ohji General Hospital.Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University of Science.Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University of Science.Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University of Science.Purpose: The chemotherapeutic agent irinotecan is hydrolyzed to its active form SN-38 by human carboxyesterases, but SN-38 is converted into the inactive form SN-38G by hepatic UDP-glucuronosyltransferases (UGTs). The aim of the present study was to evaluate the inhibitory effects of two b-glucuronidase-treated Japanese traditional herbal medicines (kampo), Hange-Shashin-To (TJ-14) and Sairei-To (TJ-114) on SN-38 glucuronidation, and the deglycosylation of baicalin (BG) and glycyrrhizic acid (GL) derived from TJ-14 and TJ-114 to form their respective aglycones, baicalein (BA) and glycyrrhetinic acid (GA). Methods: The inhibitory effects of b-glucuronidase-treated TJ-14 and TJ-114 on SN-38 glucuronidation by human liver microsomes were examined. BA and GA, which were enzymatically converted from BG and GL present in TJ-14 and TJ-114, were examined in the same manner. Furthermore, the enzymatic activities were measured by using recombinant UGT1A1 and UGT1A9 isoforms instead of human liver microsomes. BA, GA, SN-38, and their glycosides/glucuronides were analyzed with an LC-MS system. Results: As regards the linear initial reaction rate, SN-38 glucuronidation by human liver microsomes was significantly inhibited by the addition of b-glucuronidase-untreated TJ-14 and TJ-114, but was more strongly inhibited by the addition of b-glucuronidase-treated TJ-14 and TJ-114. The results of LC-MS analysis and pharmacokinetic studies suggested that BA is the main inhibitor of SN-38 glucuronidation. In the Dixon plot, BA showed competitive inhibition of SN-38 glucuronidation, and the inhibition constant was 8.70 ± 3.24 mM. Previous reports, studies of recombinant UGT isoforms indicated that SN-38 glucuronidation was mainly catalyzed by UGT1A1. Conclusions: These findings strongly suggested that SN-38 glucuronidation is inhibited by BA. BA could act as a pharmacokinetic regulating factor associated with SN-38 glucuronidation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/29783 |
| spellingShingle | Takashi Satoh Ayaka Igarashi Misaki Tanno Koki Yamada Natsuko Takahashi-Suzuki Kazuhiro Watanabe Inhibitory Effects of Baicalein Derived from Japanese Traditional Herbal Medicine on SN-38 Glucuronidation Journal of Pharmacy & Pharmaceutical Sciences |
| title | Inhibitory Effects of Baicalein Derived from Japanese Traditional Herbal Medicine on SN-38 Glucuronidation |
| title_full | Inhibitory Effects of Baicalein Derived from Japanese Traditional Herbal Medicine on SN-38 Glucuronidation |
| title_fullStr | Inhibitory Effects of Baicalein Derived from Japanese Traditional Herbal Medicine on SN-38 Glucuronidation |
| title_full_unstemmed | Inhibitory Effects of Baicalein Derived from Japanese Traditional Herbal Medicine on SN-38 Glucuronidation |
| title_short | Inhibitory Effects of Baicalein Derived from Japanese Traditional Herbal Medicine on SN-38 Glucuronidation |
| title_sort | inhibitory effects of baicalein derived from japanese traditional herbal medicine on sn 38 glucuronidation |
| url | https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/29783 |
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