New insights into the biology and pharmacology of the multidrug resistance protein (MRP) from gene knockout models.
Growing interest in the MRP (multidrug resistance protein) gene stems from its importance in multidrug resistance to chemotherapy, its possible use in gene therapy, and its relationship with the glutathione system. The recent generation of mrp gene knockout models in vitro and in vivo is providing information on the mechanism of action and the physiological function(s) of mrp. The importance of mrp in protection of normal tissues from the toxicity of the anticancer agent etoposide has been established. A total block of mrp has been found to be compatible with life, suggesting that MRP inhibitors can be safely used for treating cancer patients. In some sub-classes of leukocytes, mrp contributes to the transport of leukotriene C4, an endogenous glutathione-S-conjugate. However, the baseline expression of mrp does not appear to contribute to the export of glutathione-S-conjugates of alkylating agents, and thus does not exert a protective role against their toxicity. Besides being capable of exporting certain glutathione-S-conjugates, mrp also catalyzes the co-transport of GSH and drug and, presumably, a presently unknown endogenous metabolite(s).
Rappa
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Department of Tumor Biology, Norwegian Radium Hospital, Montebello, Oslo.
Finch
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Sartorelli
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Lorico
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D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D019450:Genes, MDR; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism; D026901:Membrane Transport Proteins; D019216:Metals, Heavy / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015221:Potassium Channels / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D019216:Metals, Heavy; D015221:Potassium Channels; C086860:glutathione transporter; D017997:Leukotriene C4; D005047:Etoposide; D005978:Glutathione