ABSTRACT:Multidrug resistance proteins (MRPs) are members of the "C" branch of the ATP-binding cassette transporter superfamily. Human MRP1 transports a wide range of natural product drugs and structurally diverse conjugated and unconjugated organic anions. Its closest relative is MRP3. Despite their structural similarity, the homologs differ substantially in their substrate specificity. It is noteworthy that MRP1 transports glutathione (GSH) and GSH conjugates and displays GSH-stimulated transport of a number of unconjugated and conjugated compounds. In contrast, MRP3 does not transport GSH and is a poor transporter of GSH conjugates. The ATP-binding cassette (ABC) transporter, multidrug resistance protein (MRP) 1 was identified in a human small cell lung cancer cell line, H69AR, that exhibited cross-resistance to a broad range of natural product-type drugs (Cole et al., 1992). MRP1 was highly overexpressed in H69AR cells and after gene transfer studies was shown to cause a multidrug resistance phenotype Grant et al., 1994). MRP1 has since been found to be expressed in many solid tumors and hematological malignancies, and MRP1 is a negative prognostic indicator of treatment outcome in some .In vitro, MRP1 confers resistance to many structurally and functionally diverse natural product chemotherapeutic agents, including anthracyclines, Vinca alkaloids, and epipodophyllotoxins. MRP1 also actively transports a range of glutathione (GSH)-, glucuronide-, and sulfate-conjugated organic anions . The GSHconjugated, cysteinyl leukotriene C 4 (LTC 4 ) is the best characterized physiological substrate of MRP1 (Leier et al., 1994;Loe et al., 1996b). Other potential physiological substrates include the peptides, GSH and oxidized GSH, the glucuronide conjugate 17-estradiol 17-(-D-glucuronide) (E 2 17G), and the steroid sulfate estrone 3-sulfate (E 1 3SO 4 ) (Leier et al., 1994(Leier et al., , 1996Loe et al., 1996a;Qian et al., 2001b). MRP1 also transports chemotherapeutic agents to which it confers resistance, such as methotrexate (MTX), vincristine, daunorubicin, and etoposide (VP-16) (Loe et al., 1996b;Rappa et al., 1997;Hooijberg et al., 1999;Renes et al., 1999). Transport of certain substrates, both unconjugated (e.g., vincristine and VP-16) and conjugated (e.g., E 1 3SO 4 ), is stimulated by GSH (Loe et al., 1996bSakamoto et al., 1999;Qian et al., 2001b;Zelcer et al., 2003). In some cases (e.g., vincristine), the GSH-dependent substrate may reciprocally stimulate GSH transport, whereas in others (e.g., E 1 3SO 4 ) no stimulation is observed (Loe et al., 1998;Qian et al., 2001b). MRP1 is a member of the "C" branch of the ABC superfamily, Article, publication date, and citation information can be found at