Induction of multidrug resistance gene expression in rat liver cells in response to acute treatment by the DNA-damaging agent methyl methanesulfonate

Biochemical and Biophysical Research Communications
Olivier FardelAndré Guillouzo

Abstract

Expression of multidrug resistance (mdr) genes encoding the P-glycoprotein (P-gp) drug efflux pump was analysed in cultured rat liver epithelial cells acutely treated by the DNA-damaging agent methyl methanesulfonate (MMS). Exposure to this alkylating agent used at 30 microg/ml for 12 or 24 h was shown to enhance mdr mRNA levels in rat liver cells without alteration of cell viability. Induction of mdr transcripts occurred through increased expression of the mdr1b gene as indicated by reverse transcriptase-polymerase chain reaction analysis using rat mdr gene-specific primers and was not associated with up-regulation of cytochrome P-450 1A1, thereby suggesting that this detoxifying enzyme and P-gp were not coordinately regulated by MMS. In addition, the DNA-damaging agent was found to enhance in a dose-dependent manner cellular efflux of the P-gp substrate rhodamine 123, which was inhibited by the P-gp inhibitor verapamil, thus providing evidence that exposure to MMS led to increased P-gp-related drug transport in rat liver cells. The up-regulation of functional P-gp expression occurring in MMS-treated liver cells may be interpreted as a part of the cellular response to DNA damage.

References

Dec 1, 1978·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·E Morel-ChanyM F Szajnert
Jan 1, 1992·Reviews of Physiology, Biochemistry and Pharmacology·P HerrlichH J Rahmsdorf
May 1, 1991·British Journal of Cancer·K Nooter, H Herweijer
Jan 1, 1990·Pharmacology & Therapeutics·A B Okey
Nov 2, 1988·Journal of the National Cancer Institute·R K Burt, S S Thorgeirsson
Nov 1, 1971·Experimental Cell Research·G M WilliamsJ H Weisburger
Jan 1, 1994·Advances in Clinical Chemistry·W T Bellamy, W S Dalton
Jan 15, 1994·European Journal of Biochemistry·O FardelA Guillouzo
Apr 21, 1993·Journal of the National Cancer Institute·P M Chaudhary, I B Roninson
Jan 1, 1993·Annual Review of Biochemistry·M M Gottesman, I Pastan
Nov 8, 1996·Biochemical Pharmacology·D SchrenkS S Thorgeirsson
Apr 1, 1997·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·J A Silverman, D Schrenk
May 15, 1997·European Journal of Biochemistry·O FardelA Guillouzo

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.