Divergent Effects of Nitric Oxide Donors on the Biliary Efflux Transporters in Isolated Perfused Rat Livers: Nitric Oxide-Independent Inhibition of ABC Transporters by Sodium Nitroprusside
Rhodamine 123 (RH-123) and its glucuronidated metabolite (RH-Glu) are excreted into the bile via the ABC efflux transporters P-glycoprotein (P-gp) and multidrug resistance-related protein type 2 (Mrp2), respectively. In this study, we investigated the short-term (2 h) effects of a low or high concentration of nitric oxide (NO) donors sodium nitroprusside (SNP) and isosorbide dinitrate (ISDN) on the hepatobiliary disposition of RH-123 and its metabolite in an isolated perfused rat liver model. Additionally, the effects of ISDN on the hepatobiliary disposition of 5 (and 6)-carboxy- 2,7-dichlorofluorescein (CDF), a specific marker of Mrp2, were investigated in the same model. Whereas SNP caused a substantial (85-90%) reduction in the P-gp- and Mrp2-mediated transport of RH-123 and RH-Glu, respectively, ISDN did not affect either of these transporters. However, ISDN reduced the biliary recovery of RH-Glu, most likely because of inhibition of the formation of the metabolite. Further studies showed that the effects of SNP on these transporters are due to a substantial (88%) depletion of hepatic ATP levels by this NO donor. Additionally, studies using CDF revealed an almost identical hepatobiliary disposition of this Mrp2 marker in the presence or absence of ISDN. It is concluded that short-term exposure of rat livers to NO does not affect the functions of the efflux transporters P-gp and Mrp2. The observed inhibitory effects of SNP on the functions of both P-gp and Mrp2 are via an NO-independent mechanism.
Keywords: Nitric oxide, efflux transporters, P-glycoprotein, multidrug resistance-related protein type 2, isolated perfused rat liver, rhodamine 123, rhodamine glucuronide, 5 (and 6)-carboxy-2',7'-dichlorofluorescein, Sodium Nitroprusside, glucuronidated metabolite, bile, isosorbide dinitrate, hepatobiliary disposition, hepatic ATP, lipophilic chemical mediator, cholesterol, alcohol, cytochrome P450 (P450), cytokines, organic cation transporter (Oct), hepatocytes, xenobiotics, isosorbide dini-trate (ISDN), ketamine, xylazine, alanine aminotransferase, aspartate aminotransferase, sodium taurocholate, high-performance liquid chromatography (HPLC), fluorometry, deionized water, Biliary clearance (CLbile), hepatic clearance (CLh), Dunnett's post-hoc analysis, AUC, perfusate concentrations, biliary excretion rate-time profiles, liver concentration ratio, hepatic transporters, mRNA, MRP2 protein, dextrorphan, 3-hydroxymorphinan, dextromethorphan, photodegradation, cyanide, ATP-dependent processes, Na+/K+ ATPase activity, mitochondrial transmembrane poten-tial, mitochondria, Oatp-mediated mechanism, sinusoids, guanylase cyclase, ABC efflux transporters, Kupffer cells, gadolinium
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