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Vol. 30, Issue 7, 838-844, July 2002
Deptartment of Pharmacology, Toxicology, and Therapeutics,
University of Kansas Medical Center, Kansas City, Kansas
Multiple drug resistance (mdr) genes encode P-glycoprotein, which
is responsible for resistance to some cancer chemotherapeutic drugs and
efflux of xenobiotics of cells. Thus, mdr can protect organs from
xenobiotics. In rats, there are two mdr1 genes capable of xenobiotic
transport, mdr1a and mdr1b. The purpose of this study was to
determine the tissue distribution of rat mdr1a and mdr1b mRNA and
whether microsomal enzyme inducers that increase phase I and II
drug-metabolizing enzymes coordinately regulate mdr1a and/or mdr1b. The
mRNA levels of mdr1a and mdr1b were determined using branched-DNA
signal amplification technology. The highest level of expression of
mdr1a mRNA was observed in the gastrointestinal tract, with levels
increasing, respectively, from duodenum, jejunum, and ileum to large
intestine. Expression levels of mdr1a mRNA in the cerebral cortex,
cerebellum, kidney, lung, and liver were less than one-tenth of that in
the ileum. The tissue distribution of mdr1b mRNA was similar to mdr1a
with highest expression in the gastrointestinal tract but only about
3-fold higher than in most other tissues. The induction of mdr1a and
mdr1b mRNA transcripts in liver, kidney, and ileum by treatment of rats
with 18 chemicals representing aryl hydrocarbon receptor ligands,
constitutive androstane receptor ligands, pregnane X receptor ligands,
peroxisome proliferator-activated receptor ligands,
electrophile-response-element activators, and CYP4502E1 inducers was
assessed. Hepatic, renal, and intestinal expression of mdr1a and mdr1b
mRNA were not significantly altered by treatment of rats with any of
these classes of ligands. In conclusion, the primary expression of rat
mdr1 genes is in the gastrointestinal tract where they are thought to
function to decrease the absorption of some xenobiotics. Rat mdr1 gene
expression is not readily increased by microsomal enzyme inducers in
rats through coordinate mechanisms with phase I and II
drug-metabolizing enzymes.
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