Functional Characterization of 21 Rare Allelic <em<CYP1A2</em< Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin <em<O</em<-Deethylation
Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Masaki Kumondai [verfasserIn] Evelyn Marie Gutiérrez Rico [verfasserIn] Eiji Hishinuma [verfasserIn] Yuya Nakanishi [verfasserIn] Shuki Yamazaki [verfasserIn] Akiko Ueda [verfasserIn] Sakae Saito [verfasserIn] Shu Tadaka [verfasserIn] Kengo Kinoshita [verfasserIn] Daisuke Saigusa [verfasserIn] Tomoki Nakayoshi [verfasserIn] Akifumi Oda [verfasserIn] Noriyasu Hirasawa [verfasserIn] Masahiro Hiratsuka [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
In: Journal of Personalized Medicine - MDPI AG, 2012, 11(2021), 8, p 690 |
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| Übergeordnetes Werk: |
volume:11 ; year:2021 ; number:8, p 690 |
| Links: |
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| DOI / URN: |
10.3390/jpm11080690 |
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| Katalog-ID: |
DOAJ030065674 |
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| 520 | |a Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin <i<O</i<-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. | ||
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10.3390/jpm11080690 doi (DE-627)DOAJ030065674 (DE-599)DOAJ264a651c85094779ac36d00cdeca004a DE-627 ger DE-627 rakwb eng Masaki Kumondai verfasserin aut Functional Characterization of 21 Rare Allelic <em<CYP1A2</em< Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin <em<O</em<-Deethylation 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin <i<O</i<-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. cytochrome P450 1A2 genetic variation phenacetin drug metabolism Medicine R Evelyn Marie Gutiérrez Rico verfasserin aut Eiji Hishinuma verfasserin aut Yuya Nakanishi verfasserin aut Shuki Yamazaki verfasserin aut Akiko Ueda verfasserin aut Sakae Saito verfasserin aut Shu Tadaka verfasserin aut Kengo Kinoshita verfasserin aut Daisuke Saigusa verfasserin aut Tomoki Nakayoshi verfasserin aut Akifumi Oda verfasserin aut Noriyasu Hirasawa verfasserin aut Masahiro Hiratsuka verfasserin aut In Journal of Personalized Medicine MDPI AG, 2012 11(2021), 8, p 690 (DE-627)71862713X (DE-600)2662248-8 20754426 nnns volume:11 year:2021 number:8, p 690 https://doi.org/10.3390/jpm11080690 kostenfrei https://doaj.org/article/264a651c85094779ac36d00cdeca004a kostenfrei https://www.mdpi.com/2075-4426/11/8/690 kostenfrei https://doaj.org/toc/2075-4426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 8, p 690 |
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10.3390/jpm11080690 doi (DE-627)DOAJ030065674 (DE-599)DOAJ264a651c85094779ac36d00cdeca004a DE-627 ger DE-627 rakwb eng Masaki Kumondai verfasserin aut Functional Characterization of 21 Rare Allelic <em<CYP1A2</em< Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin <em<O</em<-Deethylation 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin <i<O</i<-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. cytochrome P450 1A2 genetic variation phenacetin drug metabolism Medicine R Evelyn Marie Gutiérrez Rico verfasserin aut Eiji Hishinuma verfasserin aut Yuya Nakanishi verfasserin aut Shuki Yamazaki verfasserin aut Akiko Ueda verfasserin aut Sakae Saito verfasserin aut Shu Tadaka verfasserin aut Kengo Kinoshita verfasserin aut Daisuke Saigusa verfasserin aut Tomoki Nakayoshi verfasserin aut Akifumi Oda verfasserin aut Noriyasu Hirasawa verfasserin aut Masahiro Hiratsuka verfasserin aut In Journal of Personalized Medicine MDPI AG, 2012 11(2021), 8, p 690 (DE-627)71862713X (DE-600)2662248-8 20754426 nnns volume:11 year:2021 number:8, p 690 https://doi.org/10.3390/jpm11080690 kostenfrei https://doaj.org/article/264a651c85094779ac36d00cdeca004a kostenfrei https://www.mdpi.com/2075-4426/11/8/690 kostenfrei https://doaj.org/toc/2075-4426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 8, p 690 |
| allfields_unstemmed |
10.3390/jpm11080690 doi (DE-627)DOAJ030065674 (DE-599)DOAJ264a651c85094779ac36d00cdeca004a DE-627 ger DE-627 rakwb eng Masaki Kumondai verfasserin aut Functional Characterization of 21 Rare Allelic <em<CYP1A2</em< Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin <em<O</em<-Deethylation 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin <i<O</i<-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. cytochrome P450 1A2 genetic variation phenacetin drug metabolism Medicine R Evelyn Marie Gutiérrez Rico verfasserin aut Eiji Hishinuma verfasserin aut Yuya Nakanishi verfasserin aut Shuki Yamazaki verfasserin aut Akiko Ueda verfasserin aut Sakae Saito verfasserin aut Shu Tadaka verfasserin aut Kengo Kinoshita verfasserin aut Daisuke Saigusa verfasserin aut Tomoki Nakayoshi verfasserin aut Akifumi Oda verfasserin aut Noriyasu Hirasawa verfasserin aut Masahiro Hiratsuka verfasserin aut In Journal of Personalized Medicine MDPI AG, 2012 11(2021), 8, p 690 (DE-627)71862713X (DE-600)2662248-8 20754426 nnns volume:11 year:2021 number:8, p 690 https://doi.org/10.3390/jpm11080690 kostenfrei https://doaj.org/article/264a651c85094779ac36d00cdeca004a kostenfrei https://www.mdpi.com/2075-4426/11/8/690 kostenfrei https://doaj.org/toc/2075-4426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 8, p 690 |
| allfieldsGer |
10.3390/jpm11080690 doi (DE-627)DOAJ030065674 (DE-599)DOAJ264a651c85094779ac36d00cdeca004a DE-627 ger DE-627 rakwb eng Masaki Kumondai verfasserin aut Functional Characterization of 21 Rare Allelic <em<CYP1A2</em< Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin <em<O</em<-Deethylation 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin <i<O</i<-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. cytochrome P450 1A2 genetic variation phenacetin drug metabolism Medicine R Evelyn Marie Gutiérrez Rico verfasserin aut Eiji Hishinuma verfasserin aut Yuya Nakanishi verfasserin aut Shuki Yamazaki verfasserin aut Akiko Ueda verfasserin aut Sakae Saito verfasserin aut Shu Tadaka verfasserin aut Kengo Kinoshita verfasserin aut Daisuke Saigusa verfasserin aut Tomoki Nakayoshi verfasserin aut Akifumi Oda verfasserin aut Noriyasu Hirasawa verfasserin aut Masahiro Hiratsuka verfasserin aut In Journal of Personalized Medicine MDPI AG, 2012 11(2021), 8, p 690 (DE-627)71862713X (DE-600)2662248-8 20754426 nnns volume:11 year:2021 number:8, p 690 https://doi.org/10.3390/jpm11080690 kostenfrei https://doaj.org/article/264a651c85094779ac36d00cdeca004a kostenfrei https://www.mdpi.com/2075-4426/11/8/690 kostenfrei https://doaj.org/toc/2075-4426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 8, p 690 |
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10.3390/jpm11080690 doi (DE-627)DOAJ030065674 (DE-599)DOAJ264a651c85094779ac36d00cdeca004a DE-627 ger DE-627 rakwb eng Masaki Kumondai verfasserin aut Functional Characterization of 21 Rare Allelic <em<CYP1A2</em< Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin <em<O</em<-Deethylation 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin <i<O</i<-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. cytochrome P450 1A2 genetic variation phenacetin drug metabolism Medicine R Evelyn Marie Gutiérrez Rico verfasserin aut Eiji Hishinuma verfasserin aut Yuya Nakanishi verfasserin aut Shuki Yamazaki verfasserin aut Akiko Ueda verfasserin aut Sakae Saito verfasserin aut Shu Tadaka verfasserin aut Kengo Kinoshita verfasserin aut Daisuke Saigusa verfasserin aut Tomoki Nakayoshi verfasserin aut Akifumi Oda verfasserin aut Noriyasu Hirasawa verfasserin aut Masahiro Hiratsuka verfasserin aut In Journal of Personalized Medicine MDPI AG, 2012 11(2021), 8, p 690 (DE-627)71862713X (DE-600)2662248-8 20754426 nnns volume:11 year:2021 number:8, p 690 https://doi.org/10.3390/jpm11080690 kostenfrei https://doaj.org/article/264a651c85094779ac36d00cdeca004a kostenfrei https://www.mdpi.com/2075-4426/11/8/690 kostenfrei https://doaj.org/toc/2075-4426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 8, p 690 |
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Functional Characterization of 21 Rare Allelic <em<CYP1A2</em< Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin <em<O</em<-Deethylation |
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Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin <i<O</i<-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. |
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Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin <i<O</i<-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. |
| abstract_unstemmed |
Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin <i<O</i<-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. |
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| title_short |
Functional Characterization of 21 Rare Allelic <em<CYP1A2</em< Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin <em<O</em<-Deethylation |
| url |
https://doi.org/10.3390/jpm11080690 https://doaj.org/article/264a651c85094779ac36d00cdeca004a https://www.mdpi.com/2075-4426/11/8/690 https://doaj.org/toc/2075-4426 |
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Evelyn Marie Gutiérrez Rico Eiji Hishinuma Yuya Nakanishi Shuki Yamazaki Akiko Ueda Sakae Saito Shu Tadaka Kengo Kinoshita Daisuke Saigusa Tomoki Nakayoshi Akifumi Oda Noriyasu Hirasawa Masahiro Hiratsuka |
| author2Str |
Evelyn Marie Gutiérrez Rico Eiji Hishinuma Yuya Nakanishi Shuki Yamazaki Akiko Ueda Sakae Saito Shu Tadaka Kengo Kinoshita Daisuke Saigusa Tomoki Nakayoshi Akifumi Oda Noriyasu Hirasawa Masahiro Hiratsuka |
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| up_date |
2024-07-04T01:27:05.611Z |
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