Upregulation of P-glycoprotein in rat hepatoma ρ° cells: Implications for drug-DNA interactions

Rat hepatoma cells lacking mitochondrial DNA (ρ° cells) were used as a model system to examine the possible roles of mitochondrial DNA as a target for the DNA‐acting anticancer drug Adriamycin (doxorubicin). The ρ° cells were 45‐fold less sensitive to Adriamycin than the parental ρ+ cells containing mitochondrial DNA. Other non‐DNA‐acting drugs also exhibited similar behaviour, and this was shown to be due to a multidrug resistance (MDR) phenotype in the ρ° cells. This was indicated by confocal microscopy where ρ+ cells exhibited thirteenfold higher cellular levels of Adriamycin than ρ° cells. Upregulation (tenfold) of P‐glycoprotein in ρ° cells was also confirmed by Northern dot blot analysis. Since the MDR phenotype is present in ρ° cells and upregulation of P‐glycoprotein is maintained in these cells, ρ° cells are not a good model system for drug‐DNA studies (where the drug is susceptible to extrusion by P‐glycoprotein), and any such results obtained with this system must be treated with considerable caution. J. Cell. Biochem. 69:463–469, 1998. © 1998 Wiley‐Liss, Inc.