title: Interaction of oligomeric breast cancer resistant protein (BCRP) with adjudin: a male contraceptive with anti-cancer activity.
abstract: Breast cancer resistant protein (BCRP, ABCG2) is an ATP-binding cassette (ABC) transporter, which together with two other ABC efflux drug pumps, namely P-glycoprotein (P-gp, ABCB1) and multidrug resistance-related protein 1 (MRP1, ABCC1) is the most important multidrug resistance protein foun d in eukaryotic cells including cells in the testis. However, unlike P-gp and MRP1, which are components of the Sertoli cell blood-testis barrier (BTB), BCRP is not expressed at the BTB in rodents and human testes. Instead, BCRP is expressed by peritubular myoid cells and endothelial cells of the lymphatic vessel in the tunica propria, residing outside the BTB. As such, the testis is equipped with two levels of defense against xenobiotics or drugs, preventing these harmful substances from entering the adluminal compartment to perturb meiosis and post-meiotic spermatid development: one at the level of the BTB conferred by P-gp and MRP1 and one at the tunica propria conferred by BCRP. The presence of drug transporters at the tunica propria as well as at the Sertoli cell BTB thus poses significant obstacles in developing non-hormonal contraceptives if these drugs (e.g., adjudin) exert their effects in germ cells behind the BTB, such as in the adluminal (apical) compartment of the seminiferous epithelium. Herein, we summarize recent findings pertinent to adjudin, a non-hormonal male contraceptive, and molecular interactions of adjudin with BCRP so that this information can be helpful to devise delivery strategies to evade BCRP in the tunica propria to improve its bioavailability in the testis.
authors.forename: Yan Ho
authors.initials: YH
authors.lastname: Cheng
authors.forename: Pranitha
authors.initials: P
authors.lastname: Jenardhanan
authors.forename: Premendu P
authors.initials: PP
authors.lastname: Mathur
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Qian
authors.forename: Weiliang
authors.initials: W
authors.lastname: Xia
authors.forename: Bruno
authors.initials: B
authors.lastname: Silvestrini
authors.affiliation: The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, 1230 York Ave, New York 10065, USA. y-cheng@popcbr.rockefeller.edu.
authors.forename: Chuen Yan
authors.initials: CY
authors.lastname: Cheng
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000988:Antispermatogenic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D001682:Biological Availability; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007191:Indazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013091:Spermatogenesis / Q000187:drug effects*; D013737:Testis / Q000187:drug effects* / Q000378:metabolism
chemical_list: C432482:1-(2,4-dichlorobenzyl)indazole-3-carbohydrazide; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D000988:Antispermatogenic Agents; D006834:Hydrazines; D007191:Indazoles; D008024:Ligands; D009363:Neoplasm Proteins