MODULATION OF P-GLYCOPROTEIN AND MDR1B MESSENGER-RNA EXPRESSION BY GROWTH-FACTORS IN PRIMARY RAT HEPATOCYTE CULTURE

P-glycoproteins encoded by members of the mdr gene family function as membrane-situated transport proteins, isoforms of which are involved i n conferring a form of multidrug resistance by participating in secret ion of various xenobiotics. In primary rat hepatocytes maintained in s erum-free culture, accumulation of immunodetectable P-glycoprotein and mdr1b mRNA occurred in a time-dependent manner and was accompanied by a substantial decrease in retention of the mdr1 substrate rhodamine 1 23. However, incubation of cells with epidermal growth factor (EGF) or with insulin-like growth factor I (IGF-I) markedly enhanced time-depe ndent accumulation of P-glycoprotein and mdr1b mRNA. Furthermore, EGF- treated cells exhibited decreased intracellular rhodamine 123 retentio n, an effect partially inhibited by the chemosensitizer verapamil. The se data suggest that an increase in (a) functional transporter(s) elic iting transport of mdr1 substrates occurs under EGF. (C) 1995 Academic Press, Inc.