RT Journal Article
SR Electronic
T1 Carriers Involved in Targeting the Cytostatic Bile Acid-Cisplatin Derivativescis-Diammine-chloro-cholylglycinate-platinum(II) andcis-Diammine-bisursodeoxycholate-platinum(II) toward Liver Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 853
OP 860
DO 10.1124/mol.61.4.853
VO 61
IS 4
A1 Oscar Briz
A1 Maria Angeles Serrano
A1 Noemi Rebollo
A1 Bruno Hagenbuch
A1 Peter J. Meier
A1 Hermann Koepsell
A1 Jose J.G. Marin
YR 2002
UL http://molpharm.aspetjournals.org/content/61/4/853.abstract
AB Molecular bases for targeting bile acid-cisplatin derivatives Bamet-R2 [cis-diammine-chloro-cholylglycinate-platinum(II)] and Bamet-UD2 [cis-diammine-bisursodeoxycholate-platinum(II)] toward liver cells were investigated. Carriers for bile acids [human Na+-taurocholate cotransporting polypeptide (NTCP)], organic anions [organic anion transporting polypeptide (OATP)], and organic cations [organic cation transporter (OCT)] were expressed inXenopus laevis oocytes (XO) and Chinese hamster ovary (CHO) cells. Drug uptake was measured by flameless atomic absorption of platinum. Rat Oatp1- or rat Ntcp-transfected CHO cells were able to take up Bamets, but not cisplatin, severalfold more efficiently than wild-type cells. This uptake was enhanced by butyrate-induced expression of both carriers. Uptake of both Bamets by Ntcp-transfected CHO cells was stimulated by extracellular sodium. The amount of Bamets, but not cisplatin, taken up by XO was enhanced when expressing OATP-A, OATP-C, NTCP, OCT1, or OCT2, a nonhepatic OCT isoform used for comparative purposes. Bamet uptake by XO was inhibited by known substrates of these carriers (glycocholate for NTCP and OATP-C, ouabain for OATP-A, and quinine for OCT1 and OCT2). Drug uptake versus substrate concentration revealed saturation kinetics (K m was in the 8–58 μM range), with the following order of efficiency of transport (V max/K m) for Bamet-R2: OATP-C > OCT2 > OATP-A > NTCP > OCT1; and the following order of efficiency of transport for Bamet-UD2: OATP-C > OCT2 > OATP-A > OCT1 > NTCP. Increasing the generation of cationic forms of Bamets by incubation in the absence of chloride increased drug uptake by OATP-A, OCT1, and OCT2 but reduced that achieved by NTCP and OATP-C. These results suggest a role for carriers of organic anions and cations in Bamet-R2 and Bamet-UD2 uptake, which may determine their ability to accumulate in liver tumor cells and/or be taken up and efficiently excreted by hepatocytes.