title: Interactions of glycyrrhizin with organic anion transporting polypeptides of rat and human liver.
abstract: Glycyrrhizin (GL) is used in Japan for the treatment of chronic hepatitis C. Following intravenous administration, GL is eliminated mainly by excretion into bile. Hepatocyte uptake of GL is a carrier-mediated process with characteristics resembling the organic anion transporting polypeptides (OATPs, solute carrier gene family SLC21A). We, therefore, studied whether GL is a potential transport substrate of the OATPs of rat and human liver. Because transport of GL could not be measured directly, GL-mediated cis-inhibition of [3H]estrone-3-sulfate or [35S]bromosulfophthalein uptake was analyzed kinetically in Xenopus laevis oocytes injected with cRNA coding for OATPs. GL inhibited [3H]estrone-3-sulfate uptake by 75-100% in oocytes expressing rat Oatp4, human OATP-C or human OATP8, members of the OATP1B subfamily that are expressed predominantly in hepatocytes. Dixon plots indicated a non-competitive type of inhibition, with Ki values of 6.1, 15.9 and 12.5 μmol/l, respectively. In contrast, GL inhibition of rat Oatp1, Oatp2 and Oatp3 and human OATP-A and OATP-B was only between 0 and 53%. In conclusion, GL is an inhibitor and, therefore, potentially a transport substrate of the liver-specific OATPs in rat and man. The rate at which GL is taken up into the liver may depend upon the function and expression levels of these hepatocellular OATPs.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital, CH-8091, Zurich, Switzerland
authors.forename: Manfred G.
authors.initials: MG
authors.lastname: Ismair
authors.forename: Carmen
authors.initials: C
authors.lastname: Stanca
authors.forename: Huy R.
authors.initials: HR
authors.lastname: Ha
authors.forename: Eberhard L.
authors.initials: EL
authors.lastname: Renner
authors.forename: Peter J.
authors.initials: PJ
authors.lastname: Meier
authors.forename: Gerd A.
authors.initials: GA
authors.lastname: Kullak-Ublick