title: Role of P-glycoprotein at the blood-testis barrier on adjudin distribution in the testis: a revisit of recent data.
abstract: The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in mammals including rodents and humans. It is used to sequester meiosis I and II, postmeiotic spermatid development via spermiogenesis and the release of sperm at spermiation from the systemic circulation, such that these events take place in an immune-privileged site in the adluminal (apical) compartment behind the BTB, segregated from the host immune system. Additionally, drug transporters, namely efflux (e.g., P-glycoprotein) and influx (e.g., Oatp3) pumps, many of which are integral membrane proteins in Sertoli cells at the BTB also work cooperatively to restrict the entry of drugs, toxicants, chemicals, steroids and other xenobiotics into the adluminal compartment. As such, the BTB that serves as an important physiological and selective barrier to protect germ cell development also poses a "hurdle" in male contraceptive development. For instance, adjudin, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide, a potential nonhormonal male contraceptive that exerts its effects on germ cell adhesion, most notably at the Sertoli cell-spermatid interface, to induce "premature" germ cell loss from the seminiferous epithelium mimicking spermiation, has a relatively poor bioavailability largely because of the BTB. Since male contraceptives (e.g., adjudin) will be used by healthy men for an extended period of his life span after puberty, a better understanding on the BTB is necessary in order to effectively deliver drugs across this blood-tissue barrier in particular if these compounds exert their effects on developing germ cells in the adluminal compartment. This can also reduce long-term toxicity and health risk if the effective dosing can be lowered in order to widen the margin between its safety and efficacy. Herein, we summarize latest findings in this area of research, we also provide a critical evaluation on research areas that deserve attention in future studies.
authors: Center for Biomedical Research, Population Council, New York, New York, USA.
authors: Linlin
authors: L
authors: Su
authors: Pranitha
authors: P
authors: Jenardhanan
authors: Dolores D
authors: DD
authors: Mruk
authors: Premendu P
authors: PP
authors: Mathur
authors: Yan-Ho
authors: YH
authors: Cheng
authors: Ka-Wai
authors: KW
authors: Mok
authors: Michele
authors: M
authors: Bonanomi
authors: Bruno
authors: B
authors: Silvestrini
authors: C Yan
authors: CY
authors: Cheng
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D022005:Adherens Junctions / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D001814:Blood-Testis Barrier / Q000187:drug effects / Q000378:metabolism*; D003272:Contraceptive Agents, Male / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology*; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013087:Spermatids / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism*
chemical_list: C432482:1-(2,4-dichlorobenzyl)indazole-3-carbohydrazide; D018435:ATP Binding Cassette Transporter, Subfamily B; D003272:Contraceptive Agents, Male; D006834:Hydrazines; D007191:Indazoles; D046912:Multiprotein Complexes
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