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-glycopro tein (P-gp) drug efflux pump was analysed in cultured rat liver epithe lial cells acutely treated by the DNA-damaging agent methyl methanesul fonate (MMS). Exposure to this alkylating agent used at 30 mu g/ml for 12 or 24 h was shown to enhance mdr mRNA levels in rat liver cells wi thout alteration of cell viability. Induction of mdr transcripts occur red through increased expression of the mdr1b gene as indicated by rev erse transcriptase-polymerase chain reaction analysis using rat mdr ge ne-specific primers and was not associated with upregulation of cytoch rome P-450 1A1, thereby suggesting that this detoxifying enzyme and P- gp were not coordinately regulated by RIMS, In addition, the DNA-damag ing agent was found to enhance in a dose-dependent manner cellular eff lux of the P-gp substrate rhodamine 123, which was inhibited by the P- gp inhibitor verapamil, thus providing evidence that exposure to RIMS led to increased P-gp-related drug transport in rat liver cells. The u p-regulation of functional P-gp expression occurring in RIMS-treated l iver cells may be interpreted as a part of the cellular response to DN A damage. (C) 1998 Academic Press.