Effect of interferons on P-glycoprotein-mediated rhodamine-123 efflux in cultured rat hepatocytes

✍ Scribed by Yukiko Akazawa; Hiroko Kawaguchi; Maki Funahashi; Yoshihiko Watanabe; Kiyoshi Yamaoka; Mitsuru Hashida; Yoshinobu Takakura

• Publisher: John Wiley and Sons
• Year: 2002
• Tongue: English
• Weight: 139 KB
• Volume: 91
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.10199

✦ Synopsis

The effect of interferon (IFN)-beta and IFN-gamma on P-glycoprotein (P-gp)-mediated efflux of rhodamin-123(Rho-123), a typical substrate of P-gp, was studied in rat hepatocytes in primary culture. After treatment with IFN-beta, IFN-gamma, or both for 3 days, steady-state levels of Rho-123, incorporated into the hepatocytes, were measured to evaluate the P-gp activity. Whereas IFN-beta did not affect the intracellular level of Rho-123, IFN-gamma treatment caused a significant increase of the level, suggesting that IFN-gamma treatment suppresses the expression of P-gp or its activity. A combination of the two types of IFN exhibited a similar effect to that of IFN-gamma alone. The effect of IFN-gamma was still observed in the presence of H(2)O(2), which enhances the expression and activity of P-gp. Immunoblot analysis using a monoclonal antibody C219 revealed, however, that P-gp expression was increased after treatment with IFN-gamma, but only slightly by IFN-beta treatment. These results suggest that the enhanced Rho-123 uptake of rat primary hepatocytes induced by IFN-gamma does not result from reduced expression of P-gp but, rather, from impaired maturation or dysfunction of the efflux transporter.