Effect of interferons on P-glycoprotein-mediated rhodamine-123 efflux in cultured rat hepatocytes.
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.
Akazawa
Yukiko
Y
Department of Biopharmaceutics and Drug Metabolism, Molecular Microbiology and Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Kawaguchi
Hiroko
H
Funahashi
Maki
M
Watanabe
Yoshihiko
Y
Yamaoka
Kiyoshi
K
Hashida
Mitsuru
M
Takakura
Yoshinobu
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D002478:Cells, Cultured; D005456:Fluorescent Dyes / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D020112:Rhodamine 123 / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005456:Fluorescent Dyes; D007370:Interferon Type I; D011994:Recombinant Proteins; D020112:Rhodamine 123; D007371:Interferon-gamma; D006861:Hydrogen Peroxide