Regulation by dexamethasone of P‐glycoprotein expression in cultured rat hepatocytes

We have examined P‐glycoprotein (P‐gp) expression and function in cultured rat hepatocytes in response to dexamethasone (DEX), which is known to modulate various liver functions. Northern blot analyses revealed high levels of P‐gp mRNAs in cultured untreated liver cells in comparison to those found in freshly isolated hepatocytes, while DEX‐treated hepatoeytes also displayed elevated, although weaker, P‐gp levels. Similarly, Western blotting analysis indicated high levels of P‐gp in liver cells maintained in the absence of DEX. The use of mdr gene‐specific probes allowed us to show that DEX‐modulated P‐gp induction in cultured hepatocytes involved mostly, if not specifically, mdrl gene regulation. Doxorubicin P‐gp‐mediated efflux analyses revealed lower intracellular doxorubicin accumulation in DEX‐untreated liver cells than in DEX‐treated cells, thus indicating that over‐expressed P‐gp was functional. These data clearly show that DEX treatment strongly modulates P‐gp expression in primary rat hepatocyte cultures through a specific effect on the mdrl gene.