Induction of multidrug resistance gene expression in rat liver cells in response to acute treatment by the DNA-damaging agent methyl methanesulfonate.
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.
Fardel
O
O
Unité INSERM U456 Détoxication et Réparation Tissulaire, Laboratoire de Physiologie, Faculté des Sciences Pharmaceutiques et Biologiques, 2 Avenue du Pr L. Bernard, Rennes, 35043, France. oliver.fardel@univ-rennes1.fr
Payen
L
L
Courtois
A
A
Lecureur
V
V
Guillouzo
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D008099:Liver / Q000187:drug effects*; D008741:Methyl Methanesulfonate / Q000494:pharmacology*; D009153:Mutagens / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009153:Mutagens; D012333:RNA, Messenger; D012235:Rhodamines; D020112:Rhodamine 123; D008741:Methyl Methanesulfonate; D014700:Verapamil; D019363:Cytochrome P-450 CYP1A1