Multispecific amphipathic substrate transport by an organic anion transporter of human liver.
BACKGROUND
Hepatic uptake of differently charged amphipathic endo- and xenobiotics 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 hepatocellular uptake of differently charged amphipathic substrates.


OBJECTIVE
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 estrone-3-sulfate, ouabain and the organic cation N-(4,4-azo-n-pentyl)-21-ajmalinium was compared in OATP-expressing and uninjected (or water injected) control oocytes.


RESULTS
Our results indicate that OATP, in addition to bromosulfophthalein and bile salts, can also transport anionic estrone-3-sulfate (Km approximately 59 microM), neutral ouabain (K(m) approximately 5.5 mM) and cationic N-(4,4-azo-n-pentyl)-21-ajmalinium. For each of these compounds, OATP-mediated uptake was cis-inhibited by the OATP substrate taurochenodeoxycholate and the transport activities correlated well with the amounts of cRNA injected.


CONCLUSIONS
Similar to the rat liver oatp, the human liver OATP can also mediate multispecific and charge-independent uptake of lipophilic amphipathic organic compounds. Thus, OATP may play an important role in the first pass clearance of drugs and other xenobiotics by the human liver.
Bossuyt
X
X
Department of Medicine, University Hospital, Zurich, Switzerland.
Müller
M
M
Meier
P J
PJ
D000818:Animals; D027321:Anion Transport Proteins; D001391:Azo Compounds / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003001:Cloning, Molecular; D004563:Electrochemistry; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D009865:Oocytes / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013655:Taurochenodeoxycholic Acid / Q000378:metabolism; D015262:Xenobiotics / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
D027321:Anion Transport Proteins; D001391:Azo Compounds; D002352:Carrier Proteins; D015262:Xenobiotics; D013655:Taurochenodeoxycholic Acid