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We demonstrated that tienilic acid, a diuretic drug withdrawn from the market because of hepatic failure, enhanced hyperbilirubinemia in Eisai hyperbilirubinuria rats (EHBR) with a defect of canalicular multidrug resistance-associated protein 2 (Mrp2). In contrast, no remarkable changes were noted in Sprague-Dawley (SD) rats, the parent strain for EHBR. To investigate a mechanism underlying this enhanced hyperbilirubinemia, we focused on comprehensive effects of tienilic acid on clinicopathological aspects and expression of hepatic transporters. Other than eventual hyperbilirubinemia with slightly increased biliary bilirubin, a single oral treatment of EHBR with tienilic acid at 300 mg/kg caused no changes in serum alanine aminotransferase and alkaline phosphatase, bile flow rate and biliary bile acid secretion, or hepatic morphology. In analyses of mRNA expression of the hepatic transporters, elevated Mrp3 expression in EHBR correlated with an increase in serum total bilirubin, suggesting increased bilirubin transport from the liver into the peripheral blood flow. Hepatic heme oxygenase-1 (Ho-1) mRNA, a stress-induced isoform of the rate-limiting enzyme in the catabolism of heme to bilirubin, was markedly upregulated in EHBR at the same dose at which increased serum bilirubin was seen. A time-course study revealed that marked induction of Ho-1 occurred earlier than that of Mrp3, followed by an increase in serum bilirubin. These results suggest that hepatic Mrp3 and Ho-1 may contribute to tienilic acid-enhanced hyperbilirubinemia in EHBR by inducing increased bilirubin transport from the liver into the blood stream, preceded by potentiation of bilirubin formation in the liver.

toxicological sciences

Tienilic Acid Enhances Hyperbilirubinemia in Eisai Hyperbilirubinuria Rats through Hepatic Multidrug Resistance–Associated Protein 3 and Heme Oxygenase-1 Induction