title: In-vivo and in-vitro evidence of a carrier-mediated efflux transport system for oestrone-3-sulphate across the blood-cerebrospinal fluid barrier.
abstract: The efflux transport of oestrone-3-sulphate, a steroid hormone sulphate, across the blood-cerebrospinal fluid barrier has been examined following its intracerebroventricular administration. [3H]Oestrone-3-sulphate was eliminated from cerebrospinal fluid (CSF) with an apparent efflux clearance of 205 microL min(-1) per rat. There was 25% of unmetabolized [3H]oestrone-3-sulphate in the plasma 5 min after intracerebroventricular administration, indicating that at least a part of [3H]oestrone-3-sulphate is transported from CSF to the circulating blood across the blood-CSF barrier. This efflux transport was inhibited by co-administration of excess oestrone-3-sulphate (25 mM 10 microL = 0.25 micromol) into rat cerebral ventricle. To characterize the oestrone-3-sulphate transport process, an in-vitro uptake experiment was performed using isolated rat choroid plexus. Oestrone-3-sulphate uptake by isolated rat choroid plexus was found to be a saturable process with a Michaelis-Menten constant (Km) of 18.1 +/- 6.3 microM, and a maximum uptake rate (Vmax) of 48.0 +/- 15.1 pmol min(-1) microL(-1) of tissue. The oestrone-3-sulphate transport process was temperature dependent and was inhibited by metabolic inhibitors such as 2,4-dinitrophenol and rotenone, suggesting an energy dependence. This uptake process was also inhibited by steroid hormone sulphates (1 mM dehydroepiandrosterone sulphate and 1 mM oestrone sulphate), bile acids (1 mM taurocholic acid and 1 mM cholic acid) and organic anions (1 mM sulphobromophthalein and 1 mM phenolsulphonphthalein), whereas 1 mM p-aminohippuric acid, 1 mM p-nitrophenol sulphate, 0.1 mM methotrexate and the cardiac glycoside, 2.5 microM digoxin, had little effect. In conclusion, these results provide evidence that oestrone-3-sulphate is transported from CSF to the circulating blood across the blood-CSF barrier via a carrier-mediated efflux transport system.
authors.affiliation: Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kitazawa
authors.forename: K
authors.initials: K
authors.lastname: Hosoya
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: T
authors.initials: T
authors.lastname: Terasaki
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000502:physiology; D002250:Carbon Radioisotopes; D002301:Cardiac Glycosides / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology*; D002555:Cerebrospinal Fluid / Q000378:metabolism; D002831:Choroid Plexus / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004970:Estrone / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D007328:Insulin / Q000493:pharmacokinetics; D008297:Male; D010637:Phenolsulfonphthalein / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology; D013448:Sulfobromophthalein / Q000494:pharmacology; D013696:Temperature; D013997:Time Factors; D014316:Tritium; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D002250:Carbon Radioisotopes; D002301:Cardiac Glycosides; D002352:Carrier Proteins; D007328:Insulin; D014475:Uncoupling Agents; D012402:Rotenone; D013448:Sulfobromophthalein; D014316:Tritium; D004970:Estrone; D003687:Dehydroepiandrosterone; D010637:Phenolsulfonphthalein; D019297:2,4-Dinitrophenol; C017296:estrone sulfate