Carcinogenesis, Vol 18, 2255-2263, Copyright © 1997 by Oxford University Press
E Santoni-Rugiu and JA Silverman
The multidrug resistance (mdr) genes encode P-glycoproteins, integral
membrane proteins which function as drug efflux transporters. Exposure of
animals in vivo and cells in vitro to a variety of xenobiotics leads to
increased mdr1 gene expression and higher levels of P-glycoprotein. This
response may protect cells from the cytotoxic effects of these compounds.
In this investigation we functionally expressed the rat mdr1b gene in NIH
3T3 cells and assessed the ability of the encoded P- glycoprotein to
protect these cells from the cytotoxicity of xenobiotics known to induce
mdr1b expression. In long-term colony survival assays, stably expressed
mdr1b conferred resistance to cytotoxic drugs such as colchicine,
vinblastine and doxorubicin, but not to 5-fluorouracil nor to the
carcinogens aflatoxin B1 and N-hydroxy- acetylaminofluorene. The mdr
reversal agent verapamil restored cytotoxicity of colchicine, doxorubicin,
actinomycin D, vinblastine and taxol, but had no effect on the sensitivity
of these cells to 5- fluorouracil, aflatoxin B1 or
N-hydroxy-acetylaminofluorene. In a competitive transport assay, verapamil
and, to a lesser extent, colchicine blocked the increased efflux of the
fluorescent dye rhodamine 123 from mdr1b-transfected cells, whereas
aflatoxin B1 did not compete for this export. These data demonstrate that
expression of the rat mdr1b encoded P-glycoprotein can protect cells from a
diverse group of compounds previously identified to be mdr substrates,
however, other effective inducers of mdr expression, such as aflatoxin B1
and N- hydroxy-acetylaminofluorene, remain potent cytotoxins despite high
levels of P-glycoprotein. The fact that compounds which are not themselves
substrates can induce P-glycoprotein expression may have implications for
pharmacokinetic interactions and chemotherapy.
ARTICLES
Functional characterization of the rat mdr1b encoded P-glycoprotein: not all inducing agents are substrates
Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
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