Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells.

Pieter Wielinga; G. Reid; E. E. Challa; I. van der Heijden; L. van Deemter; M. de Haas; C. Mol; A. J. Kuil; E. Groeneveld; J. D. Schuetz; C. Brouwer; R. A. De Abreu; J. Wijnholds; J. H. Beijnen; P. Borst

Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells.

Pieter Wielinga, G. Reid, E. E. Challa, I. van der Heijden, L. van Deemter, M. de Haas, C. Mol, A. J. Kuil, E. Groeneveld, J. D. Schuetz, C. Brouwer, R. A. De Abreu, J. Wijnholds, J. H. Beijnen, P. Borst

Netherlands Cancer Institute

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Mercaptopurines have been used as anticancer agents for more than 40 years, and most acute lymphoblastic leukemias are treated with 6-mercaptopurine (6MP) or 6-thioguanine (TG). Overexpression of the two related multidrug resistance proteins MRP4 and MRP5 has been shown to confer some resistance against mercaptopurines, which has been attributed to extrusion of mercaptopurine metabolites by these transporters. We have analyzed the mercaptopurine metabolites formed in human embryonic kidney cells and determined which metabolites are extruded by MRP4 and MRP5. Incubation with 6MP led to the formation of thioinosine and thioxanthosine metabolites and we found that thio-IMP was transported by both MRP4 and MRP5; MRP5 showed the highest transport rate. In contrast, only MRP5 transported thioxanthosine monophosphate (tXMP). During incubation with TG, the monophosphorylated form of thioguanosine was transported by both MRP4 and MRP5; the highest transport rate was for MRP4. Similarly, only 6-methyl-thio-IMP was formed during incubation with 6-methyl mercaptopurine riboside. This compound was a substrate for both MRP4 and MRP5; MRP4 showed the highest transport rate. Our results show that all major thiopurine monophosphates important in the efficacy of mercaptopurine treatment are transported by MRP4 and MRP5, although the substrate specificity of the two transporters differs in detail.

Original language	English
Journal	Molecular Pharmacology
Volume	62
Issue number	6
Pages (from-to)	1321-1331
ISSN	0026-895X
Publication status	Published - 2002
Externally published	Yes

Keywords

thioxanthosine monophosphate
acute lymphoblastic leukemia Leukemia, Lymphocytic, Acute (MeSH) blood and lymphatic disease, neoplastic disease
Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] HEK293 cell line cell line embryonic kidney
6-mercaptopurine 50-44-2 antineoplastic-drug resistance
6-thioguanine 154-42-7 antineoplastic-drug resistance
multidrug resistance protein 4 MRP4
multidrug resistance protein 5 MRP5
thiopurine metabolism
thiopurine monophosphates
10062, Biochemistry studies - Nucleic acids, purines and pyrimidines
12512, Pathology - Therapy
13002, Metabolism - General metabolism and metabolic pathways
15006, Blood - Blood, lymphatic and reticuloendothelial pathologies
22002, Pharmacology - General
22005, Pharmacology - Clinical pharmacology
24004, Neoplasms - Pathology, clinical aspects and systemic effects
24008, Neoplasms - Therapeutic agents and therapy
24010, Neoplasms - Blood and reticuloendothelial neoplasms
Pharmacology
Tumor Biology

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Wielinga, P., Reid, G., Challa, E. E., van der Heijden, I., van Deemter, L., de Haas, M., Mol, C., Kuil, A. J., Groeneveld, E., Schuetz, J. D., Brouwer, C., De Abreu, R. A., Wijnholds, J., Beijnen, J. H., & Borst, P. (2002). Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells. Molecular Pharmacology, 62(6), 1321-1331.

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abstract = "Mercaptopurines have been used as anticancer agents for more than 40 years, and most acute lymphoblastic leukemias are treated with 6-mercaptopurine (6MP) or 6-thioguanine (TG). Overexpression of the two related multidrug resistance proteins MRP4 and MRP5 has been shown to confer some resistance against mercaptopurines, which has been attributed to extrusion of mercaptopurine metabolites by these transporters. We have analyzed the mercaptopurine metabolites formed in human embryonic kidney cells and determined which metabolites are extruded by MRP4 and MRP5. Incubation with 6MP led to the formation of thioinosine and thioxanthosine metabolites and we found that thio-IMP was transported by both MRP4 and MRP5; MRP5 showed the highest transport rate. In contrast, only MRP5 transported thioxanthosine monophosphate (tXMP). During incubation with TG, the monophosphorylated form of thioguanosine was transported by both MRP4 and MRP5; the highest transport rate was for MRP4. Similarly, only 6-methyl-thio-IMP was formed during incubation with 6-methyl mercaptopurine riboside. This compound was a substrate for both MRP4 and MRP5; MRP4 showed the highest transport rate. Our results show that all major thiopurine monophosphates important in the efficacy of mercaptopurine treatment are transported by MRP4 and MRP5, although the substrate specificity of the two transporters differs in detail.",

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author = "Pieter Wielinga and G. Reid and Challa, {E. E.} and {van der Heijden}, I. and {van Deemter}, L. and {de Haas}, M. and C. Mol and Kuil, {A. J.} and E. Groeneveld and Schuetz, {J. D.} and C. Brouwer and {De Abreu}, {R. A.} and J. Wijnholds and Beijnen, {J. H.} and P. Borst",

year = "2002",

language = "English",

volume = "62",

pages = "1321--1331",

journal = "Molecular Pharmacology",

issn = "0026-895X",

publisher = "American Society for Pharmacology and Experimental Therapeutics",

number = "6",

}

Wielinga, P, Reid, G, Challa, EE, van der Heijden, I, van Deemter, L, de Haas, M, Mol, C, Kuil, AJ, Groeneveld, E, Schuetz, JD, Brouwer, C, De Abreu, RA, Wijnholds, J, Beijnen, JH & Borst, P 2002, 'Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells.', Molecular Pharmacology, vol. 62, no. 6, pp. 1321-1331.

TY - JOUR

T1 - Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells.

AU - Wielinga, Pieter

AU - Reid, G.

AU - Challa, E. E.

AU - van der Heijden, I.

AU - van Deemter, L.

AU - de Haas, M.

AU - Mol, C.

AU - Kuil, A. J.

AU - Groeneveld, E.

AU - Schuetz, J. D.

AU - Brouwer, C.

AU - De Abreu, R. A.

AU - Wijnholds, J.

AU - Beijnen, J. H.

AU - Borst, P.

PY - 2002

Y1 - 2002

N2 - Mercaptopurines have been used as anticancer agents for more than 40 years, and most acute lymphoblastic leukemias are treated with 6-mercaptopurine (6MP) or 6-thioguanine (TG). Overexpression of the two related multidrug resistance proteins MRP4 and MRP5 has been shown to confer some resistance against mercaptopurines, which has been attributed to extrusion of mercaptopurine metabolites by these transporters. We have analyzed the mercaptopurine metabolites formed in human embryonic kidney cells and determined which metabolites are extruded by MRP4 and MRP5. Incubation with 6MP led to the formation of thioinosine and thioxanthosine metabolites and we found that thio-IMP was transported by both MRP4 and MRP5; MRP5 showed the highest transport rate. In contrast, only MRP5 transported thioxanthosine monophosphate (tXMP). During incubation with TG, the monophosphorylated form of thioguanosine was transported by both MRP4 and MRP5; the highest transport rate was for MRP4. Similarly, only 6-methyl-thio-IMP was formed during incubation with 6-methyl mercaptopurine riboside. This compound was a substrate for both MRP4 and MRP5; MRP4 showed the highest transport rate. Our results show that all major thiopurine monophosphates important in the efficacy of mercaptopurine treatment are transported by MRP4 and MRP5, although the substrate specificity of the two transporters differs in detail.

AB - Mercaptopurines have been used as anticancer agents for more than 40 years, and most acute lymphoblastic leukemias are treated with 6-mercaptopurine (6MP) or 6-thioguanine (TG). Overexpression of the two related multidrug resistance proteins MRP4 and MRP5 has been shown to confer some resistance against mercaptopurines, which has been attributed to extrusion of mercaptopurine metabolites by these transporters. We have analyzed the mercaptopurine metabolites formed in human embryonic kidney cells and determined which metabolites are extruded by MRP4 and MRP5. Incubation with 6MP led to the formation of thioinosine and thioxanthosine metabolites and we found that thio-IMP was transported by both MRP4 and MRP5; MRP5 showed the highest transport rate. In contrast, only MRP5 transported thioxanthosine monophosphate (tXMP). During incubation with TG, the monophosphorylated form of thioguanosine was transported by both MRP4 and MRP5; the highest transport rate was for MRP4. Similarly, only 6-methyl-thio-IMP was formed during incubation with 6-methyl mercaptopurine riboside. This compound was a substrate for both MRP4 and MRP5; MRP4 showed the highest transport rate. Our results show that all major thiopurine monophosphates important in the efficacy of mercaptopurine treatment are transported by MRP4 and MRP5, although the substrate specificity of the two transporters differs in detail.

KW - thioxanthosine monophosphate

KW - acute lymphoblastic leukemia Leukemia, Lymphocytic, Acute (MeSH) blood and lymphatic disease, neoplastic disease

KW - Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] HEK293 cell line cell line embryonic kidney

KW - 6-mercaptopurine 50-44-2 antineoplastic-drug resistance

KW - 6-thioguanine 154-42-7 antineoplastic-drug resistance

KW - multidrug resistance protein 4 MRP4

KW - multidrug resistance protein 5 MRP5

KW - thiopurine metabolism

KW - thiopurine monophosphates

KW - 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines

KW - 12512, Pathology - Therapy

KW - 13002, Metabolism - General metabolism and metabolic pathways

KW - 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies

KW - 22002, Pharmacology - General

KW - 22005, Pharmacology - Clinical pharmacology

KW - 24004, Neoplasms - Pathology, clinical aspects and systemic effects

KW - 24008, Neoplasms - Therapeutic agents and therapy

KW - 24010, Neoplasms - Blood and reticuloendothelial neoplasms

KW - Pharmacology

KW - Tumor Biology

M3 - Journal article

SN - 0026-895X

VL - 62

SP - 1321

EP - 1331

JO - Molecular Pharmacology

JF - Molecular Pharmacology

IS - 6

ER -

Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells.

Abstract

Keywords

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