The MRP family and anticancer drug metabolism.
Acquirement of drug resistance by tumor cells is a major chemotherapeutic problem. It is well known that typical multidrug resistance is caused by P-glycoprotein and multidrug resistance related protein (MRP1) which belong to the ATP binding cassette (ABC) transporter family. Ishikawa proposed that the ATP-dependent glutathione-S-conjugate export pump (GS-X pump) and phase III detoxification system are essential to drug metabolism, and this constituted a new concept in drug metabolism and the detoxification of xenobiotics. The GS-X pump has been revealed to belong to the ABC transporter family and suggested to the contribution to anticancer drug resistance. The GS-X pump actively effluxes the glutathione S-platinum (GS-Pt) complex. We cloned novel ABC transporter cDNA from the PC-14/CDDP cell line, and the cloned cDNA was designated as a short-type MRP homologue, SMRP. Further investigation suggested that SMRP is a splicing variant of MRP5. The MRP5 mRNA levels in tumors from lung cancer patients treated with platinum regimen were significantly higher than in tumors from patients treated with non-platinum regimens, and the MRP5 expression levels were correlate with the GCS expression levels that is the rate-limiting step enzyme in glutathione biosynthesis. These results suggested that MRP5 take part in the function of GS-X pump. Recently many transporter molecules belong to the ABC transporter family such as MRP family have been identified, and appear to express in various human tissues. It can be presumed that their molecules are affected by the disposition and metabolism of drugs, but their substrates are still unclear. If the substrate specificity is revealed in the future, it is expected that the anticancer agents transporter, moreover anti cancer drug resistance mechanisms, can be clarified. This review is cited in the cisplatin resistance and the GS-X pump, and finally describes an overview of the MRPs substrates recently clarified, mainly about anticancer drugs.
Suzuki
T
T
Department of Analytical Biochemistry, Meiji Pharmaceutical University, Kiyose-shi, Tokyo, Japan. tssuzuki@my-pharm.ac.jp
Nishio
K
K
Tanabe
S
S
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents