Up-regulation of P-glycoprotein expression in rat liver cells by acute doxorubicin treatment.

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Fardel O, Lecureur V, Daval S, Corlu A, Guillouzo A

Up-regulation of P-glycoprotein expression in rat liver cells by acute doxorubicin treatment.

Eur J Biochem. 1997 May 15;246(1):186-92.

PubMed ID

9210482 [ View in PubMed

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Abstract

Expression of P-glycoprotein, a plasma-membrane glycoprotein involved in multidrug resistance and encoded by mdr genes, was investigated in cultured rat liver cells acutely exposed to doxorubicin. This anticancer drug was shown to increase mdr mRNA levels in a dose-dependent manner in both rat liver epithelial (RLE) cells and primary rat hepatocytes. This induction of mdr transcripts was detected as early as a 4-h exposure to doxorubicin used at 0.5 microg/ml. It occurred through increased expression of the mdr1 gene as assessed by northern blot analysis using rat mdr-gene-specific probes. In addition, RLE cells exposed to doxorubicin displayed an overexpression of a 140-kDa P-glycoprotein as demonstrated by western blotting. Moreover, doxorubicin-treated RLE cells displayed enhanced cellular efflux of the P-glycoprotein substrate rhodamine 123 that was inhibited by the P-glycoprotein blocker verapamil, thus providing evidence that doxorubicin-induced P-glycoprotein was functional in liver cells. Doxorubicin-mediated mdr mRNA induction was found to be fully inhibited by actinomycin D, thus indicating its dependence on RNA synthesis; it was demonstrated to be not associated with alteration of protein synthesis, suggesting it differed from the known mdr mRNA overexpression occurring in response to cycloheximide. In contrast to P-glycoprotein, other liver detoxification pathways such as cytochromes P-450 1A were not induced by doxorubicin treatment. These data indicate that doxorubicin can act as a potent acute inducer of functional P-glycoprotein in rat liver cells and therefore may modulate both chemosensitivity of hepatic cells and P-glycoprotein-mediated biliary secretion of xenobiotics.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Doxorubicin	P-glycoprotein 1	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details