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Biliary excretion of phenolphthalein sulfate in rats
Hiroyuki Tanaka1, Naoyo Sano, Hajime Takikawa
1Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
Abstract:
Glucuronide and glutathione conjugates have been reported to be substrates of multidrug resistance protein 2 (Mrp2), whereas sulfates of nonbile acid organic anions have never been reported as substrates of Mrp2. To further examine the substrate specificity of Mrp2, we examined the effects of bile acid sulfates on the biliary excretion of phenolphthalein sulfate in rats. The biliary excretion of phenolphthalein sulfate was markedly delayed in Eisai hyperbilirubinemic rats, an Mrp2-deficient strain, and was markedly inhibited by taurolithocholate-3-sulfate. The biliary excretion of leukotriene C(4) metabolites and sulfobromophthalein was inhibited by phenolphthalein sulfate infusion to some extent. These findings suggest that phenolphthalein sulfate is a unique sulfated nonbile acid organic anion which is a substrate of Mrp2.
Insights
Phenolphthalein sulfate, a unique compound, is identified as a substrate for multidrug resistance-associated protein 2 (Mrp2). This finding expands the known substrates of Mrp2, impacting drug transport research.
Area of Science:
- Pharmacology
- Biochemistry
- Molecular Biology
Background:
- Multidrug resistance-associated protein 2 (Mrp2) transports various organic anions, including glucuronide and glutathione conjugates.
- Sulfated non-bile acid organic anions have not been previously established as Mrp2 substrates.
Purpose of the Study:
- To investigate the substrate specificity of Mrp2 concerning sulfated non-bile acid organic anions.
- To determine if phenolphthalein sulfate is a substrate for Mrp2.
Main Methods:
- Experiments were conducted using Eisai hyperbilirubinemic rats, a strain deficient in Mrp2.
- The effects of bile acid sulfates, specifically taurolithocholate-3-sulfate, on biliary excretion were examined.
- The impact of phenolphthalein sulfate infusion on the biliary excretion of other Mrp2 substrates like leukotriene C4 metabolites and sulfobromophthalein was assessed.
Main Results:
- Biliary excretion of phenolphthalein sulfate was significantly delayed in Mrp2-deficient rats.
- Taurolithocholate-3-sulfate markedly inhibited the biliary excretion of phenolphthalein sulfate.
- Phenolphthalein sulfate infusion partially inhibited the biliary excretion of leukotriene C4 metabolites and sulfobromophthalein.
Conclusions:
- Phenolphthalein sulfate is a substrate for Mrp2.
- Phenolphthalein sulfate represents a unique class of sulfated non-bile acid organic anions transported by Mrp2.
- These findings contribute to understanding Mrp2 substrate specificity and its role in organic anion transport.