Abstract
P-glycoprotein (P-gp) is an efflux transporter with a wide substrate specificity that plays an important role in the disposition of drugs in the epithelial cells of various tissues, such as the gastrointestinal tract, liver, and kidney. One characteristic feature of this efflux transporter is that its expression and activity are modulated by various factors, including cytokines. Here, we investigated the effect of interferon-γ (IFN-γ) on the transport activity of P-gp and its expression in mice, since the cytokine is induced by various stimuli and capable of provoking a variety of cellular responses. Twenty-four hours after a single intraperitoneal injection of IFN-γ (1 × 105 U), mice were intravenously injected with [3H]digoxin, a P-gp substrate, and its pharmacokinetics was examined. IFN-γ pretreatment resulted in retardation of plasma elimination of the drug with a concomitant increase of its tissue levels in liver, kidney, and intestine. Furthermore, the excretion of [3H]digoxin into the urine and bile, but not into the intestinal lumen, was significantly reduced: the urinary and biliary excretion clearances in IFN-γ-treated mice were 65 and 55%, respectively, of those clearances in untreated mice. However, the P-gp expression levels were only slightly reduced (20–30% reduction) by IFN-γ treatment in the liver, kidney, or intestine on Western blot analysis. IFN-γ also caused a slight down-regulation (20–30% reduction) in the expression of cytochrome P450 3A (CYP3A) on Western blot analysis. Thus, a more pronounced effect may be elicited by IFN-γ for common substrates of P-gp and CYP3A.
Footnotes
-
DOI: 10.1124/jpet.103.057521.
-
ABBREVIATIONS:: P-gp, P-glycoprotein; CYP3A, cytochrome P450 3A; IFN, interferon; AUC, area under the curve; CL, total body clearance; PKC, protein kinase C; NO, nitric oxide; IL, interleukin; TNF-α, tumor necrosis factor; MRP, multidrug resistance protein.
- Received July 26, 2003.
- Accepted September 30, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|