Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals

Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CY...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Masaki Kumondai [verfasserIn] Akio Ito [verfasserIn] Evelyn Marie Gutiérrez Rico [verfasserIn] Eiji Hishinuma [verfasserIn] Akiko Ueda [verfasserIn] Sakae Saito [verfasserIn] Tomoki Nakayoshi [verfasserIn] Akifumi Oda [verfasserIn] Shu Tadaka [verfasserIn] Kengo Kinoshita [verfasserIn] Masamitsu Maekawa [verfasserIn] Nariyasu Mano [verfasserIn] Noriyasu Hirasawa [verfasserIn] Masahiro Hiratsuka [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	cytochrome P450 2C9 genetic variation ( tolbutamide drug metabolism

Übergeordnetes Werk:	In: Journal of Personalized Medicine - MDPI AG, 2012, 11(2021), 2, p 94
Übergeordnetes Werk:	volume:11 ; year:2021 ; number:2, p 94

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/jpm11020094

Katalog-ID:	DOAJ013313940

Internformat


LEADER	01000caa a22002652 4500
001	DOAJ013313940
003	DE-627
005	20240414083637.0
007	cr uuu---uuuuu
008	230226s2021 xx \|\|\|\|\|o 00\| \|\|eng c
024	7		\|a 10.3390/jpm11020094 \|2 doi
035			\|a (DE-627)DOAJ013313940
035			\|a (DE-599)DOAJ49b4209f10d64421befb5eca97b5ea8c
040			\|a DE-627 \|b ger \|c DE-627 \|e rakwb
041			\|a eng
100	0		\|a Masaki Kumondai \|e verfasserin \|4 aut
245	1	0	\|a Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals
264		1	\|c 2021
336			\|a Text \|b txt \|2 rdacontent
337			\|a Computermedien \|b c \|2 rdamedia
338			\|a Online-Ressource \|b cr \|2 rdacarrier
520			\|a Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.
650		4	\|a cytochrome P450 2C9
650		4	\|a genetic variation
650		4	\|a (<i<S</i<)-warfarin
650		4	\|a tolbutamide
650		4	\|a drug metabolism
653		0	\|a Medicine
653		0	\|a R
700	0		\|a Akio Ito \|e verfasserin \|4 aut
700	0		\|a Evelyn Marie Gutiérrez Rico \|e verfasserin \|4 aut
700	0		\|a Eiji Hishinuma \|e verfasserin \|4 aut
700	0		\|a Akiko Ueda \|e verfasserin \|4 aut
700	0		\|a Sakae Saito \|e verfasserin \|4 aut
700	0		\|a Tomoki Nakayoshi \|e verfasserin \|4 aut
700	0		\|a Akifumi Oda \|e verfasserin \|4 aut
700	0		\|a Shu Tadaka \|e verfasserin \|4 aut
700	0		\|a Kengo Kinoshita \|e verfasserin \|4 aut
700	0		\|a Masamitsu Maekawa \|e verfasserin \|4 aut
700	0		\|a Nariyasu Mano \|e verfasserin \|4 aut
700	0		\|a Noriyasu Hirasawa \|e verfasserin \|4 aut
700	0		\|a Masahiro Hiratsuka \|e verfasserin \|4 aut
773	0	8	\|i In \|t Journal of Personalized Medicine \|d MDPI AG, 2012 \|g 11(2021), 2, p 94 \|w (DE-627)71862713X \|w (DE-600)2662248-8 \|x 20754426 \|7 nnns
773	1	8	\|g volume:11 \|g year:2021 \|g number:2, p 94
856	4	0	\|u https://doi.org/10.3390/jpm11020094 \|z kostenfrei
856	4	0	\|u https://doaj.org/article/49b4209f10d64421befb5eca97b5ea8c \|z kostenfrei
856	4	0	\|u https://www.mdpi.com/2075-4426/11/2/94 \|z kostenfrei
856	4	2	\|u https://doaj.org/toc/2075-4426 \|y Journal toc \|z kostenfrei
912			\|a GBV_USEFLAG_A
912			\|a SYSFLAG_A
912			\|a GBV_DOAJ
912			\|a GBV_ILN_20
912			\|a GBV_ILN_22
912			\|a GBV_ILN_23
912			\|a GBV_ILN_24
912			\|a GBV_ILN_39
912			\|a GBV_ILN_40
912			\|a GBV_ILN_60
912			\|a GBV_ILN_62
912			\|a GBV_ILN_63
912			\|a GBV_ILN_65
912			\|a GBV_ILN_69
912			\|a GBV_ILN_73
912			\|a GBV_ILN_74
912			\|a GBV_ILN_95
912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
912			\|a GBV_ILN_151
912			\|a GBV_ILN_161
912			\|a GBV_ILN_170
912			\|a GBV_ILN_206
912			\|a GBV_ILN_213
912			\|a GBV_ILN_230
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
912			\|a GBV_ILN_602
912			\|a GBV_ILN_2014
912			\|a GBV_ILN_4012
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4322
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4325
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4367
912			\|a GBV_ILN_4700
951			\|a AR
952			\|d 11 \|j 2021 \|e 2, p 94

Indexfelder

author_variant	m k mk a i ai e m g r emgr e h eh a u au s s ss t n tn a o ao s t st k k kk m m mm n m nm n h nh m h mh
matchkey_str	article:20754426:2021----::ucinlsesetf2aeleiiy29vratietfeiaouai
hierarchy_sort_str	2021
publishDate	2021
allfields	10.3390/jpm11020094 doi (DE-627)DOAJ013313940 (DE-599)DOAJ49b4209f10d64421befb5eca97b5ea8c DE-627 ger DE-627 rakwb eng Masaki Kumondai verfasserin aut Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose. cytochrome P450 2C9 genetic variation (<i<S</i<)-warfarin tolbutamide drug metabolism Medicine R Akio Ito verfasserin aut Evelyn Marie Gutiérrez Rico verfasserin aut Eiji Hishinuma verfasserin aut Akiko Ueda verfasserin aut Sakae Saito verfasserin aut Tomoki Nakayoshi verfasserin aut Akifumi Oda verfasserin aut Shu Tadaka verfasserin aut Kengo Kinoshita verfasserin aut Masamitsu Maekawa verfasserin aut Nariyasu Mano verfasserin aut Noriyasu Hirasawa verfasserin aut Masahiro Hiratsuka verfasserin aut In Journal of Personalized Medicine MDPI AG, 2012 11(2021), 2, p 94 (DE-627)71862713X (DE-600)2662248-8 20754426 nnns volume:11 year:2021 number:2, p 94 https://doi.org/10.3390/jpm11020094 kostenfrei https://doaj.org/article/49b4209f10d64421befb5eca97b5ea8c kostenfrei https://www.mdpi.com/2075-4426/11/2/94 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 2, p 94
spelling	10.3390/jpm11020094 doi (DE-627)DOAJ013313940 (DE-599)DOAJ49b4209f10d64421befb5eca97b5ea8c DE-627 ger DE-627 rakwb eng Masaki Kumondai verfasserin aut Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose. cytochrome P450 2C9 genetic variation (<i<S</i<)-warfarin tolbutamide drug metabolism Medicine R Akio Ito verfasserin aut Evelyn Marie Gutiérrez Rico verfasserin aut Eiji Hishinuma verfasserin aut Akiko Ueda verfasserin aut Sakae Saito verfasserin aut Tomoki Nakayoshi verfasserin aut Akifumi Oda verfasserin aut Shu Tadaka verfasserin aut Kengo Kinoshita verfasserin aut Masamitsu Maekawa verfasserin aut Nariyasu Mano verfasserin aut Noriyasu Hirasawa verfasserin aut Masahiro Hiratsuka verfasserin aut In Journal of Personalized Medicine MDPI AG, 2012 11(2021), 2, p 94 (DE-627)71862713X (DE-600)2662248-8 20754426 nnns volume:11 year:2021 number:2, p 94 https://doi.org/10.3390/jpm11020094 kostenfrei https://doaj.org/article/49b4209f10d64421befb5eca97b5ea8c kostenfrei https://www.mdpi.com/2075-4426/11/2/94 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 2, p 94
allfields_unstemmed	10.3390/jpm11020094 doi (DE-627)DOAJ013313940 (DE-599)DOAJ49b4209f10d64421befb5eca97b5ea8c DE-627 ger DE-627 rakwb eng Masaki Kumondai verfasserin aut Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose. cytochrome P450 2C9 genetic variation (<i<S</i<)-warfarin tolbutamide drug metabolism Medicine R Akio Ito verfasserin aut Evelyn Marie Gutiérrez Rico verfasserin aut Eiji Hishinuma verfasserin aut Akiko Ueda verfasserin aut Sakae Saito verfasserin aut Tomoki Nakayoshi verfasserin aut Akifumi Oda verfasserin aut Shu Tadaka verfasserin aut Kengo Kinoshita verfasserin aut Masamitsu Maekawa verfasserin aut Nariyasu Mano verfasserin aut Noriyasu Hirasawa verfasserin aut Masahiro Hiratsuka verfasserin aut In Journal of Personalized Medicine MDPI AG, 2012 11(2021), 2, p 94 (DE-627)71862713X (DE-600)2662248-8 20754426 nnns volume:11 year:2021 number:2, p 94 https://doi.org/10.3390/jpm11020094 kostenfrei https://doaj.org/article/49b4209f10d64421befb5eca97b5ea8c kostenfrei https://www.mdpi.com/2075-4426/11/2/94 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 2, p 94
allfieldsGer	10.3390/jpm11020094 doi (DE-627)DOAJ013313940 (DE-599)DOAJ49b4209f10d64421befb5eca97b5ea8c DE-627 ger DE-627 rakwb eng Masaki Kumondai verfasserin aut Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose. cytochrome P450 2C9 genetic variation (<i<S</i<)-warfarin tolbutamide drug metabolism Medicine R Akio Ito verfasserin aut Evelyn Marie Gutiérrez Rico verfasserin aut Eiji Hishinuma verfasserin aut Akiko Ueda verfasserin aut Sakae Saito verfasserin aut Tomoki Nakayoshi verfasserin aut Akifumi Oda verfasserin aut Shu Tadaka verfasserin aut Kengo Kinoshita verfasserin aut Masamitsu Maekawa verfasserin aut Nariyasu Mano verfasserin aut Noriyasu Hirasawa verfasserin aut Masahiro Hiratsuka verfasserin aut In Journal of Personalized Medicine MDPI AG, 2012 11(2021), 2, p 94 (DE-627)71862713X (DE-600)2662248-8 20754426 nnns volume:11 year:2021 number:2, p 94 https://doi.org/10.3390/jpm11020094 kostenfrei https://doaj.org/article/49b4209f10d64421befb5eca97b5ea8c kostenfrei https://www.mdpi.com/2075-4426/11/2/94 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 2, p 94
allfieldsSound	10.3390/jpm11020094 doi (DE-627)DOAJ013313940 (DE-599)DOAJ49b4209f10d64421befb5eca97b5ea8c DE-627 ger DE-627 rakwb eng Masaki Kumondai verfasserin aut Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose. cytochrome P450 2C9 genetic variation (<i<S</i<)-warfarin tolbutamide drug metabolism Medicine R Akio Ito verfasserin aut Evelyn Marie Gutiérrez Rico verfasserin aut Eiji Hishinuma verfasserin aut Akiko Ueda verfasserin aut Sakae Saito verfasserin aut Tomoki Nakayoshi verfasserin aut Akifumi Oda verfasserin aut Shu Tadaka verfasserin aut Kengo Kinoshita verfasserin aut Masamitsu Maekawa verfasserin aut Nariyasu Mano verfasserin aut Noriyasu Hirasawa verfasserin aut Masahiro Hiratsuka verfasserin aut In Journal of Personalized Medicine MDPI AG, 2012 11(2021), 2, p 94 (DE-627)71862713X (DE-600)2662248-8 20754426 nnns volume:11 year:2021 number:2, p 94 https://doi.org/10.3390/jpm11020094 kostenfrei https://doaj.org/article/49b4209f10d64421befb5eca97b5ea8c kostenfrei https://www.mdpi.com/2075-4426/11/2/94 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 2, p 94
language	English
source	In Journal of Personalized Medicine 11(2021), 2, p 94 volume:11 year:2021 number:2, p 94
sourceStr	In Journal of Personalized Medicine 11(2021), 2, p 94 volume:11 year:2021 number:2, p 94
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	cytochrome P450 2C9 genetic variation (<i<S</i<)-warfarin tolbutamide drug metabolism Medicine R
isfreeaccess_bool	true
container_title	Journal of Personalized Medicine
authorswithroles_txt_mv	Masaki Kumondai @@aut@@ Akio Ito @@aut@@ Evelyn Marie Gutiérrez Rico @@aut@@ Eiji Hishinuma @@aut@@ Akiko Ueda @@aut@@ Sakae Saito @@aut@@ Tomoki Nakayoshi @@aut@@ Akifumi Oda @@aut@@ Shu Tadaka @@aut@@ Kengo Kinoshita @@aut@@ Masamitsu Maekawa @@aut@@ Nariyasu Mano @@aut@@ Noriyasu Hirasawa @@aut@@ Masahiro Hiratsuka @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	71862713X
id	DOAJ013313940
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ013313940</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240414083637.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230226s2021 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3390/jpm11020094</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ013313940</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ49b4209f10d64421befb5eca97b5ea8c</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Masaki Kumondai</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2021</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">cytochrome P450 2C9</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">genetic variation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">(<i<S</i<)-warfarin</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">tolbutamide</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">drug metabolism</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Medicine</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">R</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Akio Ito</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Evelyn Marie Gutiérrez Rico</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eiji Hishinuma</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Akiko Ueda</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Sakae Saito</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Tomoki Nakayoshi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Akifumi Oda</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Shu Tadaka</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Kengo Kinoshita</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Masamitsu Maekawa</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Nariyasu Mano</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Noriyasu Hirasawa</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Masahiro Hiratsuka</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Journal of Personalized Medicine</subfield><subfield code="d">MDPI AG, 2012</subfield><subfield code="g">11(2021), 2, p 94</subfield><subfield code="w">(DE-627)71862713X</subfield><subfield code="w">(DE-600)2662248-8</subfield><subfield code="x">20754426</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:11</subfield><subfield code="g">year:2021</subfield><subfield code="g">number:2, p 94</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.3390/jpm11020094</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/49b4209f10d64421befb5eca97b5ea8c</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://www.mdpi.com/2075-4426/11/2/94</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/2075-4426</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">11</subfield><subfield code="j">2021</subfield><subfield code="e">2, p 94</subfield></datafield></record></collection>
author	Masaki Kumondai
spellingShingle	Masaki Kumondai misc cytochrome P450 2C9 misc genetic variation misc (<i<S</i<)-warfarin misc tolbutamide misc drug metabolism misc Medicine misc R Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals
authorStr	Masaki Kumondai
ppnlink_with_tag_str_mv	@@773@@(DE-627)71862713X
format	electronic Article
delete_txt_mv	keep
author_role	aut aut aut aut aut aut aut aut aut aut aut aut aut aut
collection	DOAJ
remote_str	true
illustrated	Not Illustrated
issn	20754426
topic_title	Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals cytochrome P450 2C9 genetic variation (<i<S</i<)-warfarin tolbutamide drug metabolism
topic	misc cytochrome P450 2C9 misc genetic variation misc (<i<S</i<)-warfarin misc tolbutamide misc drug metabolism misc Medicine misc R
topic_unstemmed	misc cytochrome P450 2C9 misc genetic variation misc (<i<S</i<)-warfarin misc tolbutamide misc drug metabolism misc Medicine misc R
topic_browse	misc cytochrome P450 2C9 misc genetic variation misc (<i<S</i<)-warfarin misc tolbutamide misc drug metabolism misc Medicine misc R
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
format_main_str_mv	Text Zeitschrift/Artikel
carriertype_str_mv	cr
hierarchy_parent_title	Journal of Personalized Medicine
hierarchy_parent_id	71862713X
hierarchy_top_title	Journal of Personalized Medicine
isfreeaccess_txt	true
familylinks_str_mv	(DE-627)71862713X (DE-600)2662248-8
title	Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals
ctrlnum	(DE-627)DOAJ013313940 (DE-599)DOAJ49b4209f10d64421befb5eca97b5ea8c
title_full	Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals
author_sort	Masaki Kumondai
journal	Journal of Personalized Medicine
journalStr	Journal of Personalized Medicine
lang_code	eng
isOA_bool	true
recordtype	marc
publishDateSort	2021
contenttype_str_mv	txt
author_browse	Masaki Kumondai Akio Ito Evelyn Marie Gutiérrez Rico Eiji Hishinuma Akiko Ueda Sakae Saito Tomoki Nakayoshi Akifumi Oda Shu Tadaka Kengo Kinoshita Masamitsu Maekawa Nariyasu Mano Noriyasu Hirasawa Masahiro Hiratsuka
container_volume	11
format_se	Elektronische Aufsätze
author-letter	Masaki Kumondai
doi_str_mv	10.3390/jpm11020094
author2-role	verfasserin
title_sort	functional assessment of 12 rare allelic <i<cyp2c9</i< variants identified in a population of 4773 japanese individuals
title_auth	Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals
abstract	Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.
abstractGer	Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.
abstract_unstemmed	Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.
collection_details	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
container_issue	2, p 94
title_short	Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals
url	https://doi.org/10.3390/jpm11020094 https://doaj.org/article/49b4209f10d64421befb5eca97b5ea8c https://www.mdpi.com/2075-4426/11/2/94 https://doaj.org/toc/2075-4426
remote_bool	true
author2	Akio Ito Evelyn Marie Gutiérrez Rico Eiji Hishinuma Akiko Ueda Sakae Saito Tomoki Nakayoshi Akifumi Oda Shu Tadaka Kengo Kinoshita Masamitsu Maekawa Nariyasu Mano Noriyasu Hirasawa Masahiro Hiratsuka
author2Str	Akio Ito Evelyn Marie Gutiérrez Rico Eiji Hishinuma Akiko Ueda Sakae Saito Tomoki Nakayoshi Akifumi Oda Shu Tadaka Kengo Kinoshita Masamitsu Maekawa Nariyasu Mano Noriyasu Hirasawa Masahiro Hiratsuka
ppnlink	71862713X
mediatype_str_mv	c
isOA_txt	true
hochschulschrift_bool	false
doi_str	10.3390/jpm11020094
up_date	2024-07-03T16:57:34.738Z
_version_	1803577830660898816
fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ013313940</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240414083637.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230226s2021 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3390/jpm11020094</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ013313940</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ49b4209f10d64421befb5eca97b5ea8c</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Masaki Kumondai</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2021</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by <i<CYP2C9</i< genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These <i<CYP2C9</i< variants were heterologously expressed in 293FT cells, and the kinetic parameters (<i<K<sub<m</sub<</i<, <i<k<sub<cat</sub<</i<, <i<V<sub<max</sub<</i<, catalytic efficiency, and <i<CL<sub<int</sub<</i<) of (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (<i<S</i<)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel <i<CYP2C9</i< rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">cytochrome P450 2C9</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">genetic variation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">(<i<S</i<)-warfarin</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">tolbutamide</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">drug metabolism</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Medicine</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">R</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Akio Ito</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Evelyn Marie Gutiérrez Rico</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eiji Hishinuma</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Akiko Ueda</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Sakae Saito</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Tomoki Nakayoshi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Akifumi Oda</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Shu Tadaka</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Kengo Kinoshita</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Masamitsu Maekawa</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Nariyasu Mano</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Noriyasu Hirasawa</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Masahiro Hiratsuka</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Journal of Personalized Medicine</subfield><subfield code="d">MDPI AG, 2012</subfield><subfield code="g">11(2021), 2, p 94</subfield><subfield code="w">(DE-627)71862713X</subfield><subfield code="w">(DE-600)2662248-8</subfield><subfield code="x">20754426</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:11</subfield><subfield code="g">year:2021</subfield><subfield code="g">number:2, p 94</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.3390/jpm11020094</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/49b4209f10d64421befb5eca97b5ea8c</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://www.mdpi.com/2075-4426/11/2/94</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/2075-4426</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">11</subfield><subfield code="j">2021</subfield><subfield code="e">2, p 94</subfield></datafield></record></collection>
score	7.39849

Nicht das Richtige dabei?

Schreiben Sie uns!

Functional Assessment of 12 Rare Allelic <i<CYP2C9</i< Variants Identified in a Population of 4773 Japanese Individuals

Nicht das Richtige dabei?

Zugang & Verfügbarkeit

Vorhandene Bände

Nicht das Richtige dabei?