EFFECTS OF FLAVONOLS ON P-GLYCOPROTEIN ACTIVITY IN CULTURED RAT HEPATOCYTES

The effects of flavonols on P-glycoprotein (Pgp) activity were studied in cultured rat hepatocytes by assessing the transmembrane transport of Rhodamine-123 (R-123) and doxorubicin (DOX). In freshly-plated hepa tocytes, containing a low amount of Pgp, flavonols did not affect the cellular retention of DOX, but strongly inhibited the Pgp-mediated eff lux of R-123. In 72h-cultured hepatocytes, spontaneously overexpressin g functional Pgp, flavonols inhibited R-123 efflux in a dose-dependent manner, but significantly reduced DOX retention while increasing its efflux. A similar effect was found in hepatocytes obtained from rats i n which Pqp was induced in vivo by 2-acetamino-fluorene (AAF) or alpha -naphthyl-isothiocyanate (ANIT) treatments. These findings indicate th at flavonols, dietary compounds reported to strongly upregulate the ap parent activity of Pgp in cancer cell lines, may also modulate differe ntly the transport of putative Pgp substrates in normal rat hepatocyte s. The ability to affect the drug-extruding activity at the hepatocite canalicular membrane could be of relevance to the chemopreventive act ion of these compounds towards liver carcinogens.