Journal of Hepatology 1996; 25: 133-138 Printed in Denmark All rights resewed zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Munksgaard Copenhagen Copyright Q Europenn Association for the Study of the Liver 1996 zyxwvutsrq Journal of Hepatology ISSN 0168- 8278 zyxwvutsrqponmlk Multispecific amphipathic substrate transport by an organic anion transporter of human liver Xavier Bossuyt’, Michael Miiller” and Peter J. Meier’ ‘Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Switzerland and 2Department of Gastmenterology and Hepatology, University Hospital Groningen, Groningen, The Netherlands Background: Hepatic uptake of differently charged amphipathic endo- and xenohiotics is thought to occur via distinct carrier-mediated transport systems. Alternatively, a single rat organic anion transporting polypeptide (oatp) has recently been demonstrated to mediate hepatocel- lular uptake of differently charged amphipathic substrates. Aim: To investigate whether a cloned human liver organic anion transporting polypeptide (OATP) also can mediate charge- and class-independent hepatocellular uptake of amphipathic substrates. Methods: Xenopus laevis oocytes were injected with OATP-cRNA. Sodium-independent uptake of es- trone-3-sulfate, ouabain and the organic cation N- (4,4-azo-n-pentyl)-21-ajmalinium was compared in OATP-expressing and uninjected (or water in- jected) control oocytes. Results: Our results indicate that OATP, in addi- MAJOR A function of the liver is the clearance of various endogenous and exogenous lipophilic compounds, including many drugs. This drug clear- ance process is initiated by sinusoidal (or basolateral) Received I December 1995; revised 26 February; accepted 26 February 1996 Correspondence: Prof. Dr. P J. Meier-Abt, Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, CH-8091 Zurich, Switzer- land. Tel.: +41-l-255 3652. Fax: +41-l-255 4411. Abbreviations: APD-ajmalinium, N-(4,4-azo-n-pentyl)-21- ajmalinium; BSP, sulfobromophthalein; OATP, human liver organic anion transporting polypeptide; oatp, rat liver organic anion transporting polypeptide. * A preliminary communication of this work has been presented at the 46th Annual Meeting of the American Association for the Study of Liver Diseases, Chicago, November 1995, and has been published in abstract form in Hepatology 1995; 22,239A. tion to bromosulfophthalein and bile salts, can also transport anionic es&one-3-sulfate (Km=59 PM), neutral ouabain (Q6.5 mM) and cationic N-(4,4- azo-n-pentyl)-21-ajmalinium. For each of these compounds, OATP-mediated uptake was cis-inhib- ited by the OATP substrate taurochenodeoxycho- late and the transport activities correlated well with the amounts of cRNA injected. Conclusion: Similar to the rat liver oatp, the hu- man liver OATP can also mediate multispecific and charge-independent uptake of lipophilic am- phipathic organic compounds. Thus, OATP may play an important role in the first pass clearance of drugs and other xenobiotics by the human liver. Key words: Ajmalinium; Estrone3-sulfate; He- patic transport; Organic anion transporting poly- peptide; Ouabain; Sinusoidal membrane. membrane transport systems that are generally thought to mediate class-speci$c and charge-selec- tive hepatocellular uptake of amphipathic organic an- ions (l-4), neutral compounds (S-7) and organic cat- ions (1,6,8,9). Alternatively, it has been postulated that a single hepatocytic “multispeci$c bile acid transporter” might be responsible for sodium-inde- pendent sinusoidal uptake of organic anions (e.g. sul- fobromophthalein (BSP) and bile salts), neutral com- pounds (e.g. ouabain) and certain organic cations such as N-(4,4-azo-n-pentyl)-21-deoxy [21-3H]ajma- linium (APD-ajmalinium), a permanently charged derivative of the antiarrhythmic compound N-propyl- ajmaline (3,7,10-16). This latter hypothesis has re- cently been supported by the demonstration that a single rat liver organic anion transporting polypeptide (oatp) (17,18) can also transport a variety of differ- ently charged amphipathic organic compounds in- cluding anionic BSP, bile salts and estrogen-conju- 733