The human multidrug resistance-associated protein (MRP) gene family: From biological function to drug molecular design

The ATP-binding cassette transmembrane proteins play an important role in t ransport of drugs as well as of biologically active endogenous substances. The human multidrug resistance-associated protein (MRP) subfamily consists of at least six members, exhibiting a wide spectrum of biological functions . MRP1 operates as an ATP-dependent primary active transporter for substrat es conjugated with glucuronide, sulfate or glutathione. Leukotriene C-4 is an important endogenous substrate for MRP1. Glutathione serves as a cofacto r in MRP1-mediated drug transport as well. Genes encoding both MRP1 and the catalytic subunit of gamma -glutamylcysteine synthetase (gamma -GCS) are c oordinately regulated in cultured cancer cell lines as well as colorectal c ancer tissues from colon cancer patients. The induction of MRP1 and gamma - GCS expression by oxidative stress varies among different cell lines, and p 53 mutations are associated with elevated levels of induction. To modulate the transport function of MRP1, we have synthesized novel glutathione deriv atives as photoreactive biochemical probes targeting the transporter protei n. GIF-0019 restored the cellular sensitivity of MRP1-overexpressing drug-r esistant cancer cells to anticancer prostaglandins in vitro, which was char acterized by enhanced mRNA levels of the cyclin-dependent kinase inhibitor p21, suppressed c-myc expression and G1 arrest.