MRP1 mutated in the L0 region transports SN-38 but not leukotriene C4 or estradiol-17 (beta-D-glucuronate).
Multidrug resistance protein 1 (MRP1) is an ATP-binding cassette transporter that confers multidrug resistance on tumor cells. Much convincing evidence has accumulated that MRP1 transports most substances in a GSH-dependent manner. On the other hand, several reports have revealed that MRP1 can transport some substrates independently of GSH; however, the importance of GSH-independent transport activity is not well established and the mechanistic differences between GSH-dependent and -independent transport by MRP1 are unclear. We previously demonstrated that the amino acids W261 and K267 in the L0 region of MRP1 were important for leukotriene C4 (LTC4) transport activity of MRP1 and for GSH-dependent photolabeling of MRP1 with azidophenyl agosterol-A (azidoAG-A). In this paper, we further tested the effect of W222L, W223L and R230A mutations in MRP1, designated dmL0MRP1, on MRP1 transport activity. SN-38 is an active metabolic form of CPT-11 that is one of the most promising anti-cancer drugs. Membrane vesicles prepared from cells expressing dmL0MRP1 could transport SN-38, but not LTC4 or estradiol-17 (beta-D-glucuronate), and could not be photolabeled with azidoAG-A. These data suggested that SN-38 was transported by a different mechanism than that of GSH-dependent transport. Understanding the GSH-independent transport mechanism of MRP1, and identification of drugs that are transported by this mechanism, will be critical for combating MRP1-mediated drug resistance. We performed a pairwise comparison of compounds that are transported by MRP1 in a GSH-dependent or -independent manner. These data indicated that it may be possible to predict compounds that are transported by MRP1 in a GSH-independent manner.
Noguchi
Tomohiro
T
Department Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8544, Japan.
Ren
Xiao-Qin
XQ
Aoki
Shunji
S
Igarashi
Yoshinobu
Y
Che
Xiao-Fang
XF
Nakajima
Yuichi
Y
Takahashi
Homare
H
Mitsuo
Ryoichi
R
Tsujikawa
Kazutake
K
Sumizawa
Tomoyuki
T
Haraguchi
Misako
M
Kobayashi
Motomasa
M
Goto
Susumu
S
Kanehisa
Minoru
M
Aikou
Takashi
T
Akiyama
Shin-ichi
S
Furukawa
Tatsuhiko
T
D001483:Base Sequence; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D004958:Estradiol / Q000493:pharmacokinetics*; D006801:Humans; D000077146:Irinotecan; D017997:Leukotriene C4 / Q000493:pharmacokinetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D019920:Photoaffinity Labels
D002166:Camptothecin; D017931:DNA Primers; D004958:Estradiol; D000077146:Irinotecan; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019920:Photoaffinity Labels; C421109:multidrug resistance-associated protein 1