Suppression of multi-drug resistance gene expression in the mouse liver by 1,4-bis[2,(3,5-dichloropyridyloxy)]benzene.
P-glycoproteins encoded by the (multi-drug resistance) mdr genes play a central role in the resistance of tumor cells to a wide range of anti-cancer drugs. Modulation of P-glycoprotein function could therefore provide a means of sensitising tumor cells to chemotherapy. Studies in this context have centred around the use of compounds which antagonise the P-glycoprotein membrane transport system. To investigate the possibility of modulating P-glycoprotein expression at a transcriptional level, we investigated the effects of hormonal factors and cytochrome P450-inducing agents on hepatic expression of murine mdr 1, mdr 2 and mdr 3. Hepatic mdr 2 and mdr 3 expressions were significantly suppressed in hypophysectomised animals, indicating that pituitary hormones activate the hepatic expression of these genes. Many of the foreign compounds and anti-cancer drugs tested did not significantly induce mdr 1, 2 or 3 expression. However, it was of particular interest that a potent cytochrome P450 inducer, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, almost completely suppressed hepatic mdr 2 and 3 expressions.
Russell
A L
AL
Imperial Cancer Research Fund, University of Dundee, UK.
Henderson
C J
CJ
Smith
G
G
Wolf
C R
CR
D000818:Animals; D015152:Blotting, Northern; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D007016:Hypophysectomy; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011725:Pyridines / Q000494:pharmacology*
D011725:Pyridines; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene