P-glycoprotein regulates chemosensitivity in early developmental stages of the mouse.
The multidrug resistance (MDR) P-glycoprotein (P-gp) is an active transporter associated with chemoresistance of tumor cells. A fundamental aspect not yet entirely clarified is the physiological role of MDR-P-gp in normal mammalian tissues. In this paper we report that multidrug (chemo)resistance is already present in mouse oocytes and early cleavage embryos. Expression of MDR-specific P-gp is detectable by antibody (C219) staining from the primary oocyte onward to the eight-cell embryo. MDR-mRNA is demonstrated in mature oocytes using an Mdr1-specific cDNA probe. Functional activity of P-gp is shown by the efficacy of MDR reversers (verapamil or quinidine) in enhancement of: 1) drug accumulation (daunomycin) in all stages investigated, 2) drug cytotoxicity (daunomycin or mitomycin c-induced developmental impairment) in two-cell embryos cultured for 24 h, and 3) drug cytokinesis-blocking activity (cytochalasin D; our recent findings demonstrate cytochalasins to be substrates for P-gp and to indicate the presence of MDR by their microfilament-disrupting action on cycling cells) in four- and eight-cell embryos cultured for 24 h. Furthermore, functional involvement of P-gp in vivo is demonstrated. Concurrent administration of verapamil increases doxorubicin-induced developmental impairment in the zygote stage during the first cleavage cycle in pregnant females. Results provide evidence that MDR-P-gp has an efficient protective function in early reproduction.
Elbling
L
L
Institute for Tumor Biology-Cancer Research, University of Vienna, Austria.
Berger
W
W
Rehberger
A
A
Waldhör
T
T
Micksche
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D046508:Culture Techniques; D015638:Cytochalasin D / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D005314:Embryonic and Fetal Development / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005260:Female; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D015638:Cytochalasin D; D016685:Mitomycin; D004317:Doxorubicin; D014700:Verapamil; D003630:Daunorubicin