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.