Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6).
Mutations in human multidrug resistance protein 6 (MRP6, ABCC6), a member of the MRP family of drug efflux pumps, are the genetic basis of Pseudoxanthoma elasticum, a disease that affects elastin fibers in the skin, retina, and blood vessels. However, little is known about the functional characteristics of the protein, including its potential activity as a resistance factor for anticancer agents. Here, we report the results of investigations of the in vitro transport properties and drug resistance activity of MRP6. Using membrane vesicles prepared from Chinese hamster ovary cells transfected with MRP6 expression vector, it is shown that expression of MRP6 is specifically associated with the MgATP-dependent transport of the glutathione S-conjugates leukotriene C(4) and S-(2, 4-dinitrophenyl)glutathione and the cyclopentapeptide BQ123 but not glucuronate conjugates such as 17beta-estradiol 17-(beta-D-glucuronide). Analysis of the drug sensitivity of MRP6-transfected cells revealed low levels of resistance to several natural product agents, including etoposide, teniposide, doxorubicin, and daunorubicin. These results indicate that MRP6 is a glutathione conjugate pump that is able to confer low levels of resistance to certain anticancer agents.
Belinsky
Martin G
MG
Medical Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Chen
Zhe-Sheng
ZS
Shchaveleva
Irina
I
Zeng
Hao
H
Kruh
Gary D
GD
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001693:Biological Transport, Active; D016466:CHO Cells; D006224:Cricetinae; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000493:pharmacokinetics / Q000494:pharmacology; D017997:Leukotriene C4 / Q000493:pharmacokinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013713:Teniposide / Q000493:pharmacokinetics / Q000494:pharmacology; D014162:Transfection
D000970:Antineoplastic Agents; D005047:Etoposide; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013713:Teniposide; C102029:ABCC6 protein, human