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Vol. 282, Issue 2, 866-872, 1997

Kinetic Analysis of the Primary Active Transport of Conjugated Metabolites Across the Bile Canalicular Membrane: Comparative Study of S-(2,4-Dinitrophenyl)-glutathione and 6-Hydroxy-5,7-dimethyl-2-methylamino4-(3-pyridylmethyl)benzothiazole Glucuronide1

Kayoko Niinuma, Osamu Takenaka, Toru Horie, Kazuo Kobayashi, Yukio Kato, Hiroshi Suzuki and Yuichi Sugiyama

Faculty of Pharmaceutical Sciences, University of Tokyo (K.N., Y.K., H.S.,Y.S.), Tsukuba Research Laboratories, Eisai Co., Ltd. (O.T., T.H.) and The Institute of Scientific and Industrial Research, Osaka University (K.K.), Japan

Eisai hyperbilirubinemic rat (EHBR) is a mutant strain with a hereditary defect in canalicular multispecific organic anion transporter (cMOAT). We examined the uptake and mutual inhibition of S-(2,4-dinitrophenyl)-glutathione (DNP-SG), which is a typical substrate for cMOAT, and 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) glucuronide (E-glu) with canalicular membrane vesicles (CMV) prepared from Sprague-Dawley (SD) and EHBR rats to investigate the multiplicity of the organic anion transporter. The ATP-dependent uptake by CMV from SD rats had an apparent Km of 17.6 µM for DNP-SG and 5.7 µM for E-glu, whereas the corresponding uptake by CMV from EHBR had an apparent Km of 44.6 µM for E-glu. The effects of E-glu, 4-methylumbelliferone glucuronide (4 MUG), E3040 sulfate (E-sul) and 4-methylumbelliferone sulfate (4 MUS) on the uptake of [3H]DNP-SG were also examined. The uptake of [3H]DNP-SG was inhibited by glucuronides (E-glu and 4 MUG) in a concentration-dependent manner, although it was enhanced by the sulfate conjugates (E-sul and 4 MUS). This enhancement was shown to be caused by an increased DNP-SG affinity for the transporter. In CMV from SD rats, although ATP-dependent uptake of [3H]DNP-SG was almost completely inhibited by E-glu, that of [14C]E-glu was only reduced to about 30% of controls by DNP-SG. On the other hand, in CMV from EHBR, the ATP-dependent uptake of [14C]E-glu was not inhibited at all by DNP-SG. Kinetic analysis indicated that E-glu inhibited DNP-SG uptake competitively. In conclusion: 1) cMOAT recognizes both DNP-SG and E-glu, and another transporter present in SD rats is also involved in E-glu transport along with cMOAT; 2) the latter transporter is kinetically similar to the E-glu transporter present in EHBR; 3) E-sul enhances the uptake of DNP-SG by increasing the affinity of glucuronide for the transporter.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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