Genuine functions of P-glycoprotein (ABCB1).
P-glycoprotein (P-gp, ABCB1, MDR1) was recognized as a drug-exporting protein from cancer cells three decade ago. Apart from the multidrug transporter side effects of P-gp, normal physiological functions of P-gp have been reported. P-gp could be responsible for translocating platelet-activating factor (PAF) across the plasma membrane and PAF inhibited drug transport mediated by P-gp in cancer cells. P-gp regulated the translocation of sphingomyelin (SM) and GlcCer, and short chain C(6)-NBD-GlcCer was found in the apical medium of P-gp cells exclusively and not in the basolateral membrane. SM plays an important role in the esterification of cholesterol. High expression of P-gp prevents stem-cell differentiation, leading to the proliferation and amplification of this cell repertoire, and functional P-gp plays a fundamental role in regulating programmed cell death, apoptosis. The transporter function of P-gp is therefore necessary to protect cells from death. P-gp can translocate both C(6)-NBD-PC and C(6)-NBD-PE across the apical membrane. This PC translocation was also confirmed with [(3)H]choline radioactivity. Progesterone is not transported by P-gp, but blocks P-gp-mediated efflux of other drugs and P-gp can mediate the transport of a variety of steroids. Cells transfected with human P-gp esterified more cholesterol. P-gp might also be involved in the transport of cytokines, particularly IL-1beta, IL-2, IL-4 and IFNgamma, out of activated normal lymphocytes into the surrounding medium. P-gp expression is also associated with a volume-activated chloride channel, thus P-gp is bifunctional with both transport and channel regulators. We also present information about P-gp polymorphism and new structural concepts, "gate" and "twist", of the P-gp structure.
Mizutani
Takaharu
T
Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603 Japan. mizutani@phar.nagoya-cu.ac.jp
Masuda
Masatoshi
M
Nakai
Emi
E
Furumiya
Kenji
K
Togawa
Hiroshi
H
Nakamura
Yutaka
Y
Kawai
Yuko
Y
Nakahira
Keiko
K
Shinkai
Shigeko
S
Takahashi
Kazuhiko
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D010743:Phospholipids / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism; D011110:Polymorphism, Genetic; D013109:Sphingomyelins / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016207:Cytokines; D010743:Phospholipids; D010972:Platelet Activating Factor; D013109:Sphingomyelins; D002784:Cholesterol