6-Mercaptopurine transport in human lymphocytes: correlation with drug-induced cytotoxicity.

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Citation

Conklin LS, Cuffari C, Okazaki T, Miao Y, Saatian B, Chen TE, Tse M, Brant SR, Li X

6-Mercaptopurine transport in human lymphocytes: correlation with drug-induced cytotoxicity.

J Dig Dis. 2012 Feb;13(2):82-93. doi: 10.1111/j.1751-2980.2011.00556.x.

PubMed ID
22257476 [ View in PubMed
]
Abstract

OBJECTIVE: 6-mercaptopurine (6-MP) is efficacious in the treatment of inflammatory bowel disease (IBD). However, about one-third of patients respond poorly to therapy. This study aimed to characterize the inherent differences in 6-MP transport that may cotribute to the differences in treatment responses. METHODS: Intracellular 6-MP accumulation was assayed in Epstein-Barr virus (EBV)-transformed lymphocytes from IBD patients, using (14) C-radiolabeled 6-MP. Cell proliferation was determined by methyl thiazolyl tetrazolium (MTT) assay. Apoptosis was assayed based on the activation of caspase 3. The expressions of 15 potential 6-MP transporters were evaluated by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Intracellular 6-MP accumulation, varying significantly among patients, was carrier-dependent and partially sodium-dependent. 6-MP cytotoxicity was, at least in part, due to apoptosis and correlated with intracellular drug accumulation. The efflux transporters did not appear to contribute to the variability of intracellular drug accumulation between patients, since none correlated with drug accumulation or cytotoxicity. Rather, differential expression of five influx/uptake transporters might be a key contributor to the difference in the accumulation of and susceptibility to the drug. CONCLUSIONS: The heterogeneity of the drug transporters may be the reason for the therapeutic sensitivity of 6-MP in IBD patients. As the 6-MP uptake is a carrier-mediated and partially sodium-dependent process, future studies are necessary to evaluate the role of the putative transporters and their correlation with drug sensitivity in patients.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
AzathioprineEquilibrative nucleoside transporter 2ProteinHumans
Unknown
Substrate
Details
AzathioprineP-glycoprotein 1ProteinHumans
Unknown
Substrate
Details
AzathioprineSolute carrier family 28 member 3ProteinHumans
Unknown
Substrate
Details