Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry?

The ergothioneine transporter ETT (formerly OCTN1; human gene symbol <i<SLC22A4</i<) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). Recently, Sparreboom et al. reported that the ETT would transport nucleosides and nucleoside analogues such as cytarabi...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Julian Peter Müller [verfasserIn] Dirk Gründemann [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	ergothioneine ergothioneine transporter drug transport nucleoside transport nucleoside metabolism

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 23(2022), 9, p 4690
Übergeordnetes Werk:	volume:23 ; year:2022 ; number:9, p 4690

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms23094690

Katalog-ID:	DOAJ029067413

Internformat


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520			\|a The ergothioneine transporter ETT (formerly OCTN1; human gene symbol <i<SLC22A4</i<) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). Recently, Sparreboom et al. reported that the ETT would transport nucleosides and nucleoside analogues such as cytarabine and gemcitabine with the highest efficiency. In our assay system, we could not detect any such transport. Subsequently, Sparreboom suggested that the intracellular metabolization of the nucleosides occurs so fast that the original compounds cannot be detected by LC–MS/MS after inward transport. Our current experiments with 293 cells disprove this hypothesis. Uptake of gemcitabine was easily detected by LC–MS/MS measurements when we expressed the Na<sup<+</sup</nucleoside cotransporter CNT3 (<i<SLC28A3</i<). Inward transport was 1280 times faster than the intracellular production of gemcitabine triphosphate. The deoxycytidine kinase inhibitor 2-thio-2′-deoxycytidine markedly blocked the production of gemcitabine triphosphate. There was no concomitant surge in intracellular gemcitabine, however. This does not fit the rapid phosphorylation of gemcitabine. Uptake of cytarabine was very slow, but detection by MS was still possible. When the ETT was expressed and incubated with gemcitabine, there was no increase in intracellular gemcitabine triphosphate. We conclude that the ETT does not transport nucleosides.
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allfields	10.3390/ijms23094690 doi (DE-627)DOAJ029067413 (DE-599)DOAJ716fcd6b1b6e41b0b35b3a09da452fbe DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Julian Peter Müller verfasserin aut Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry? 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The ergothioneine transporter ETT (formerly OCTN1; human gene symbol <i<SLC22A4</i<) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). Recently, Sparreboom et al. reported that the ETT would transport nucleosides and nucleoside analogues such as cytarabine and gemcitabine with the highest efficiency. In our assay system, we could not detect any such transport. Subsequently, Sparreboom suggested that the intracellular metabolization of the nucleosides occurs so fast that the original compounds cannot be detected by LC–MS/MS after inward transport. Our current experiments with 293 cells disprove this hypothesis. Uptake of gemcitabine was easily detected by LC–MS/MS measurements when we expressed the Na<sup<+</sup</nucleoside cotransporter CNT3 (<i<SLC28A3</i<). Inward transport was 1280 times faster than the intracellular production of gemcitabine triphosphate. The deoxycytidine kinase inhibitor 2-thio-2′-deoxycytidine markedly blocked the production of gemcitabine triphosphate. There was no concomitant surge in intracellular gemcitabine, however. This does not fit the rapid phosphorylation of gemcitabine. Uptake of cytarabine was very slow, but detection by MS was still possible. When the ETT was expressed and incubated with gemcitabine, there was no increase in intracellular gemcitabine triphosphate. We conclude that the ETT does not transport nucleosides. <i<SLC22A4</i< ergothioneine ergothioneine transporter drug transport nucleoside transport nucleoside metabolism Biology (General) Chemistry Dirk Gründemann verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 9, p 4690 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:9, p 4690 https://doi.org/10.3390/ijms23094690 kostenfrei https://doaj.org/article/716fcd6b1b6e41b0b35b3a09da452fbe kostenfrei https://www.mdpi.com/1422-0067/23/9/4690 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 23 2022 9, p 4690
spelling	10.3390/ijms23094690 doi (DE-627)DOAJ029067413 (DE-599)DOAJ716fcd6b1b6e41b0b35b3a09da452fbe DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Julian Peter Müller verfasserin aut Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry? 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The ergothioneine transporter ETT (formerly OCTN1; human gene symbol <i<SLC22A4</i<) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). Recently, Sparreboom et al. reported that the ETT would transport nucleosides and nucleoside analogues such as cytarabine and gemcitabine with the highest efficiency. In our assay system, we could not detect any such transport. Subsequently, Sparreboom suggested that the intracellular metabolization of the nucleosides occurs so fast that the original compounds cannot be detected by LC–MS/MS after inward transport. Our current experiments with 293 cells disprove this hypothesis. Uptake of gemcitabine was easily detected by LC–MS/MS measurements when we expressed the Na<sup<+</sup</nucleoside cotransporter CNT3 (<i<SLC28A3</i<). Inward transport was 1280 times faster than the intracellular production of gemcitabine triphosphate. The deoxycytidine kinase inhibitor 2-thio-2′-deoxycytidine markedly blocked the production of gemcitabine triphosphate. There was no concomitant surge in intracellular gemcitabine, however. This does not fit the rapid phosphorylation of gemcitabine. Uptake of cytarabine was very slow, but detection by MS was still possible. When the ETT was expressed and incubated with gemcitabine, there was no increase in intracellular gemcitabine triphosphate. We conclude that the ETT does not transport nucleosides. <i<SLC22A4</i< ergothioneine ergothioneine transporter drug transport nucleoside transport nucleoside metabolism Biology (General) Chemistry Dirk Gründemann verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 9, p 4690 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:9, p 4690 https://doi.org/10.3390/ijms23094690 kostenfrei https://doaj.org/article/716fcd6b1b6e41b0b35b3a09da452fbe kostenfrei https://www.mdpi.com/1422-0067/23/9/4690 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 23 2022 9, p 4690
allfields_unstemmed	10.3390/ijms23094690 doi (DE-627)DOAJ029067413 (DE-599)DOAJ716fcd6b1b6e41b0b35b3a09da452fbe DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Julian Peter Müller verfasserin aut Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry? 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The ergothioneine transporter ETT (formerly OCTN1; human gene symbol <i<SLC22A4</i<) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). Recently, Sparreboom et al. reported that the ETT would transport nucleosides and nucleoside analogues such as cytarabine and gemcitabine with the highest efficiency. In our assay system, we could not detect any such transport. Subsequently, Sparreboom suggested that the intracellular metabolization of the nucleosides occurs so fast that the original compounds cannot be detected by LC–MS/MS after inward transport. Our current experiments with 293 cells disprove this hypothesis. Uptake of gemcitabine was easily detected by LC–MS/MS measurements when we expressed the Na<sup<+</sup</nucleoside cotransporter CNT3 (<i<SLC28A3</i<). Inward transport was 1280 times faster than the intracellular production of gemcitabine triphosphate. The deoxycytidine kinase inhibitor 2-thio-2′-deoxycytidine markedly blocked the production of gemcitabine triphosphate. There was no concomitant surge in intracellular gemcitabine, however. This does not fit the rapid phosphorylation of gemcitabine. Uptake of cytarabine was very slow, but detection by MS was still possible. When the ETT was expressed and incubated with gemcitabine, there was no increase in intracellular gemcitabine triphosphate. We conclude that the ETT does not transport nucleosides. <i<SLC22A4</i< ergothioneine ergothioneine transporter drug transport nucleoside transport nucleoside metabolism Biology (General) Chemistry Dirk Gründemann verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 9, p 4690 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:9, p 4690 https://doi.org/10.3390/ijms23094690 kostenfrei https://doaj.org/article/716fcd6b1b6e41b0b35b3a09da452fbe kostenfrei https://www.mdpi.com/1422-0067/23/9/4690 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 23 2022 9, p 4690
allfieldsGer	10.3390/ijms23094690 doi (DE-627)DOAJ029067413 (DE-599)DOAJ716fcd6b1b6e41b0b35b3a09da452fbe DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Julian Peter Müller verfasserin aut Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry? 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The ergothioneine transporter ETT (formerly OCTN1; human gene symbol <i<SLC22A4</i<) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). Recently, Sparreboom et al. reported that the ETT would transport nucleosides and nucleoside analogues such as cytarabine and gemcitabine with the highest efficiency. In our assay system, we could not detect any such transport. Subsequently, Sparreboom suggested that the intracellular metabolization of the nucleosides occurs so fast that the original compounds cannot be detected by LC–MS/MS after inward transport. Our current experiments with 293 cells disprove this hypothesis. Uptake of gemcitabine was easily detected by LC–MS/MS measurements when we expressed the Na<sup<+</sup</nucleoside cotransporter CNT3 (<i<SLC28A3</i<). Inward transport was 1280 times faster than the intracellular production of gemcitabine triphosphate. The deoxycytidine kinase inhibitor 2-thio-2′-deoxycytidine markedly blocked the production of gemcitabine triphosphate. There was no concomitant surge in intracellular gemcitabine, however. This does not fit the rapid phosphorylation of gemcitabine. Uptake of cytarabine was very slow, but detection by MS was still possible. When the ETT was expressed and incubated with gemcitabine, there was no increase in intracellular gemcitabine triphosphate. We conclude that the ETT does not transport nucleosides. <i<SLC22A4</i< ergothioneine ergothioneine transporter drug transport nucleoside transport nucleoside metabolism Biology (General) Chemistry Dirk Gründemann verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 9, p 4690 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:9, p 4690 https://doi.org/10.3390/ijms23094690 kostenfrei https://doaj.org/article/716fcd6b1b6e41b0b35b3a09da452fbe kostenfrei https://www.mdpi.com/1422-0067/23/9/4690 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 23 2022 9, p 4690
allfieldsSound	10.3390/ijms23094690 doi (DE-627)DOAJ029067413 (DE-599)DOAJ716fcd6b1b6e41b0b35b3a09da452fbe DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Julian Peter Müller verfasserin aut Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry? 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The ergothioneine transporter ETT (formerly OCTN1; human gene symbol <i<SLC22A4</i<) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). Recently, Sparreboom et al. reported that the ETT would transport nucleosides and nucleoside analogues such as cytarabine and gemcitabine with the highest efficiency. In our assay system, we could not detect any such transport. Subsequently, Sparreboom suggested that the intracellular metabolization of the nucleosides occurs so fast that the original compounds cannot be detected by LC–MS/MS after inward transport. Our current experiments with 293 cells disprove this hypothesis. Uptake of gemcitabine was easily detected by LC–MS/MS measurements when we expressed the Na<sup<+</sup</nucleoside cotransporter CNT3 (<i<SLC28A3</i<). Inward transport was 1280 times faster than the intracellular production of gemcitabine triphosphate. The deoxycytidine kinase inhibitor 2-thio-2′-deoxycytidine markedly blocked the production of gemcitabine triphosphate. There was no concomitant surge in intracellular gemcitabine, however. This does not fit the rapid phosphorylation of gemcitabine. Uptake of cytarabine was very slow, but detection by MS was still possible. When the ETT was expressed and incubated with gemcitabine, there was no increase in intracellular gemcitabine triphosphate. We conclude that the ETT does not transport nucleosides. <i<SLC22A4</i< ergothioneine ergothioneine transporter drug transport nucleoside transport nucleoside metabolism Biology (General) Chemistry Dirk Gründemann verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 9, p 4690 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:9, p 4690 https://doi.org/10.3390/ijms23094690 kostenfrei https://doaj.org/article/716fcd6b1b6e41b0b35b3a09da452fbe kostenfrei https://www.mdpi.com/1422-0067/23/9/4690 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 23 2022 9, p 4690
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callnumber-first	Q - Science
author	Julian Peter Müller
spellingShingle	Julian Peter Müller misc QH301-705.5 misc QD1-999 misc <i<SLC22A4</i< misc ergothioneine misc ergothioneine transporter misc drug transport misc nucleoside transport misc nucleoside metabolism misc Biology (General) misc Chemistry Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry?
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topic_title	QH301-705.5 QD1-999 Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry? <i<SLC22A4</i< ergothioneine ergothioneine transporter drug transport nucleoside transport nucleoside metabolism
topic	misc QH301-705.5 misc QD1-999 misc <i<SLC22A4</i< misc ergothioneine misc ergothioneine transporter misc drug transport misc nucleoside transport misc nucleoside metabolism misc Biology (General) misc Chemistry
topic_unstemmed	misc QH301-705.5 misc QD1-999 misc <i<SLC22A4</i< misc ergothioneine misc ergothioneine transporter misc drug transport misc nucleoside transport misc nucleoside metabolism misc Biology (General) misc Chemistry
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title	Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry?
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title_full	Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry?
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doi_str_mv	10.3390/ijms23094690
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title_sort	does intracellular metabolism render gemcitabine uptake undetectable in mass spectrometry?
callnumber	QH301-705.5
title_auth	Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry?
abstract	The ergothioneine transporter ETT (formerly OCTN1; human gene symbol <i<SLC22A4</i<) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). Recently, Sparreboom et al. reported that the ETT would transport nucleosides and nucleoside analogues such as cytarabine and gemcitabine with the highest efficiency. In our assay system, we could not detect any such transport. Subsequently, Sparreboom suggested that the intracellular metabolization of the nucleosides occurs so fast that the original compounds cannot be detected by LC–MS/MS after inward transport. Our current experiments with 293 cells disprove this hypothesis. Uptake of gemcitabine was easily detected by LC–MS/MS measurements when we expressed the Na<sup<+</sup</nucleoside cotransporter CNT3 (<i<SLC28A3</i<). Inward transport was 1280 times faster than the intracellular production of gemcitabine triphosphate. The deoxycytidine kinase inhibitor 2-thio-2′-deoxycytidine markedly blocked the production of gemcitabine triphosphate. There was no concomitant surge in intracellular gemcitabine, however. This does not fit the rapid phosphorylation of gemcitabine. Uptake of cytarabine was very slow, but detection by MS was still possible. When the ETT was expressed and incubated with gemcitabine, there was no increase in intracellular gemcitabine triphosphate. We conclude that the ETT does not transport nucleosides.
abstractGer	The ergothioneine transporter ETT (formerly OCTN1; human gene symbol <i<SLC22A4</i<) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). Recently, Sparreboom et al. reported that the ETT would transport nucleosides and nucleoside analogues such as cytarabine and gemcitabine with the highest efficiency. In our assay system, we could not detect any such transport. Subsequently, Sparreboom suggested that the intracellular metabolization of the nucleosides occurs so fast that the original compounds cannot be detected by LC–MS/MS after inward transport. Our current experiments with 293 cells disprove this hypothesis. Uptake of gemcitabine was easily detected by LC–MS/MS measurements when we expressed the Na<sup<+</sup</nucleoside cotransporter CNT3 (<i<SLC28A3</i<). Inward transport was 1280 times faster than the intracellular production of gemcitabine triphosphate. The deoxycytidine kinase inhibitor 2-thio-2′-deoxycytidine markedly blocked the production of gemcitabine triphosphate. There was no concomitant surge in intracellular gemcitabine, however. This does not fit the rapid phosphorylation of gemcitabine. Uptake of cytarabine was very slow, but detection by MS was still possible. When the ETT was expressed and incubated with gemcitabine, there was no increase in intracellular gemcitabine triphosphate. We conclude that the ETT does not transport nucleosides.
abstract_unstemmed	The ergothioneine transporter ETT (formerly OCTN1; human gene symbol <i<SLC22A4</i<) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). Recently, Sparreboom et al. reported that the ETT would transport nucleosides and nucleoside analogues such as cytarabine and gemcitabine with the highest efficiency. In our assay system, we could not detect any such transport. Subsequently, Sparreboom suggested that the intracellular metabolization of the nucleosides occurs so fast that the original compounds cannot be detected by LC–MS/MS after inward transport. Our current experiments with 293 cells disprove this hypothesis. Uptake of gemcitabine was easily detected by LC–MS/MS measurements when we expressed the Na<sup<+</sup</nucleoside cotransporter CNT3 (<i<SLC28A3</i<). Inward transport was 1280 times faster than the intracellular production of gemcitabine triphosphate. The deoxycytidine kinase inhibitor 2-thio-2′-deoxycytidine markedly blocked the production of gemcitabine triphosphate. There was no concomitant surge in intracellular gemcitabine, however. This does not fit the rapid phosphorylation of gemcitabine. Uptake of cytarabine was very slow, but detection by MS was still possible. When the ETT was expressed and incubated with gemcitabine, there was no increase in intracellular gemcitabine triphosphate. We conclude that the ETT does not transport nucleosides.
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container_issue	9, p 4690
title_short	Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry?
url	https://doi.org/10.3390/ijms23094690 https://doaj.org/article/716fcd6b1b6e41b0b35b3a09da452fbe https://www.mdpi.com/1422-0067/23/9/4690 https://doaj.org/toc/1661-6596 https://doaj.org/toc/1422-0067
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up_date	2024-07-03T20:58:33.320Z
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Uptake of cytarabine was very slow, but detection by MS was still possible. When the ETT was expressed and incubated with gemcitabine, there was no increase in intracellular gemcitabine triphosphate. 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Does Intracellular Metabolism Render Gemcitabine Uptake Undetectable in Mass Spectrometry?

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