RT Journal Article
SR Electronic
T1 Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 891
OP 896
VO 276
IS 3
A1 X Bossuyt
A1 M Müller
A1 B Hagenbuch
A1 P J Meier
YR 1996
UL http://jpet.aspetjournals.org/content/276/3/891.abstract
AB An organic anion-transporting polypeptide that mediates sodium-independent uptake of negatively charged sulfobromophthalein and bile salts has recently been cloned from rat liver (Jacquemin et al., 1994). In this study we have extended the substrate specificity studies to neutral and positively charged organic compounds with use of the Xenopus laevis oocyte expression systems. We found that the same transporting polypeptide can also transport the neutral cardiac glycoside ouabain (apparent Km approximately 1.7mM); the endogenous steroids aldosterone (Km approximately 15nM), cortisol (Km approximately 13 microM) and dexamethasone; the anionic steroid-conjugates estrone-3-sulfate (Km approximately 4.5 microM) and estradiol-17-glucuronide (Km approximately 3.0 microM) and the exogenous amphipathic organic cation N-(4,4-azo-n-pentyl)-21-deoxyajmalinium, a permanently charged photolabile derivative of the antiarrhythmic drug N-propylajmaline. These data demonstrate that the previously cloned hepatic organic anion-transporting polypeptide can in fact transport a wide range of differently charged lipophilic organic compounds including exogenous and endogenous organic anions, neutral steroids and organic cations. Hence, a single sinusoidal (or basolateral) transporting polypeptide can account, at least in part, for charge-independent steroid and drug clearance in mammalian liver.