Evaluation of effects of indoxyl sulfate and parathyroid hormone on CYP3A activity considering the influence of CYP3A5 gene polymorphisms
© 2023 British Pharmacological Society..
AIMS: Indoxyl sulfate and parathyroid hormone (PTH), which accumulate in chronic kidney disease (CKD), have been reported to reduce cytochrome P450(CYP)3A activity. Homozygotes of the CYP3A5*3 allele have reduced CYP3A5 activity compared to carriers of at least one CYP3A5*1 allele. 4β-Hydroxycholesterol (4β-OHC) has been established as an endogenous substrate reflecting CYP3A activity. 4β-OHC is produced through hydroxylation by CYP3A4 and CYP3A5 and by autoxidation of cholesterol, whereas 4α-hydroxycholesterol (4α-OHC) is produced solely by autoxidation of cholesterol. This study focused on CKD patients and evaluated the effects of plasma indoxyl sulfate and intact-PTH concentrations on plasma 4β-OHC concentration, 4β-OHC/total cholesterol ratio and 4β-OHC-4α-OHC, with consideration of the influence of CYP3A5 polymorphism.
METHODS: Sixty-three CKD patients were analysed and divided into CYP3A5 carrier group (n = 26) and non-carrier group (n = 37).
RESULTS: Plasma indoxyl sulfate significantly correlated inversely with 4β-OHC concentration and with 4β-OHC-4α-OHC in both the CYP3A5*1 carrier group (r = -0.42, P = .034; r = -0.39, P = .050, respectively) and the non-carrier group (r = -0.45, P = .0054; r = -0.39, P = .019, respectively). However, multiple regression analysis did not identify plasma indoxyl sulfate concentration as a significant independent factor associated with any of the CYP3A activity indices. There was no significant correlation between plasma intact-PTH concentration and any of the CYP3A activity indices.
CONCLUSIONS: The present results suggest that plasma indoxyl sulfate and intact-PTH concentrations do not have clinically significant effects on CYP3A activity in patients with CKD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:89 |
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| Enthalten in: |
British journal of clinical pharmacology - 89(2023), 12 vom: 14. Dez., Seite 3648-3658 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Oda, Ayako [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.11.2023 Date Revised 05.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bcp.15866 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM360226485 |
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| 245 | 1 | 0 | |a Evaluation of effects of indoxyl sulfate and parathyroid hormone on CYP3A activity considering the influence of CYP3A5 gene polymorphisms |
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| 500 | |a Date Revised 05.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 British Pharmacological Society. | ||
| 520 | |a AIMS: Indoxyl sulfate and parathyroid hormone (PTH), which accumulate in chronic kidney disease (CKD), have been reported to reduce cytochrome P450(CYP)3A activity. Homozygotes of the CYP3A5*3 allele have reduced CYP3A5 activity compared to carriers of at least one CYP3A5*1 allele. 4β-Hydroxycholesterol (4β-OHC) has been established as an endogenous substrate reflecting CYP3A activity. 4β-OHC is produced through hydroxylation by CYP3A4 and CYP3A5 and by autoxidation of cholesterol, whereas 4α-hydroxycholesterol (4α-OHC) is produced solely by autoxidation of cholesterol. This study focused on CKD patients and evaluated the effects of plasma indoxyl sulfate and intact-PTH concentrations on plasma 4β-OHC concentration, 4β-OHC/total cholesterol ratio and 4β-OHC-4α-OHC, with consideration of the influence of CYP3A5 polymorphism | ||
| 520 | |a METHODS: Sixty-three CKD patients were analysed and divided into CYP3A5 carrier group (n = 26) and non-carrier group (n = 37) | ||
| 520 | |a RESULTS: Plasma indoxyl sulfate significantly correlated inversely with 4β-OHC concentration and with 4β-OHC-4α-OHC in both the CYP3A5*1 carrier group (r = -0.42, P = .034; r = -0.39, P = .050, respectively) and the non-carrier group (r = -0.45, P = .0054; r = -0.39, P = .019, respectively). However, multiple regression analysis did not identify plasma indoxyl sulfate concentration as a significant independent factor associated with any of the CYP3A activity indices. There was no significant correlation between plasma intact-PTH concentration and any of the CYP3A activity indices | ||
| 520 | |a CONCLUSIONS: The present results suggest that plasma indoxyl sulfate and intact-PTH concentrations do not have clinically significant effects on CYP3A activity in patients with CKD | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Yoshijima, Chisato |e verfasserin |4 aut | |
| 700 | 1 | |a Sato, Haruki |e verfasserin |4 aut | |
| 700 | 1 | |a Tanaka, Ryota |e verfasserin |4 aut | |
| 700 | 1 | |a Ono, Hiroyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Tatsuta, Ryosuke |e verfasserin |4 aut | |
| 700 | 1 | |a Ando, Tadasuke |e verfasserin |4 aut | |
| 700 | 1 | |a Shin, Toshitaka |e verfasserin |4 aut | |
| 700 | 1 | |a Itoh, Hiroki |e verfasserin |4 aut | |
| 700 | 1 | |a Ohno, Keiko |e verfasserin |4 aut | |
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