[Structures and functions of xenobiotic efflux pump P-glycoprotein and MRP--important molecular targets for cancer chemotherapy].
This paper deals with the basic features of the xenobiotic efflux pump (P-glycoprotein and MRP) and the clinical significance of the search for specific modulators of these proteins. P-glycoprotein and MRP function as ATP-dependent efflux pumps that extrude cytotoxic drugs from the cells before the drugs reach their intracellular targets, thus conferring resistance to many structurally dissimilar anti-cancer drugs. These proteins are responsible for multidrug resistance of tumor cells, a major obstacle to cancer chemotherapy. To develop well-designed modulators, structural information regarding the specific drug binding sites is important. We recently found that mutations in the putative transmembrane domain (TM) 1 of human P-glycoprotein alter the drug resistance pattern. Some amino acid residues in TM1 together with TM5-6 and TM11-12 may help to govern substrate specificity. The features common to substrates for P-glycoprotein and MRP are also discussed.
Ueda
K
K
Laboratory of Biochemistry, Graduate School of Agriculture, Kyoto University, Japan.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000502:physiology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology; D018432:Drug Resistance, Multiple; D019450:Genes, MDR; D006801:Humans; D008970:Molecular Weight; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009369:Neoplasms / Q000737:chemistry / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins