DIFFERENTIAL REGULATION OF MDR GENES IN RESPONSE TO 2-ACETYLAMINOFLUORENE TREATMENT IN CULTURED RAT AND HUMAN HEPATOCYTES

Expression of P-glycoprotein (P-gp), the mdr gene product, was investi gated in primary cultures of rat and human hepatocytes exposed to 2-ac etylaminofluorene (2-AAF), Increased levels of mdr1 mRNAs were evident in 2-AAF-treated rat hepatocytes by Northern blot analysis using rat mdr gene-specific probes, while transcripts of the mdr2 and mdr3 genes mere decreased and unaffected respectively, Rat hepatocytes exposed t o 2-AAF were also found to accumulate doxorubicin, an anticancer drug known to be transported by P-gp, poorly, thereby demonstrating that 2- AAF-mediated mdr1 induction resulted in increased P-gp activity, In co ntrast to their rat counterparts, human hepatocytes obtained from 10 i ndividuals exhibited no change in both MDR1 and MDR2 mRNA levels, as w ell as in doxorubicin intracellular retention, in response to 2-AAF tr eatment, while cytochromes P-450 CYP1A1 and CYP1A2 were induced in bot h human and rat hepatocyte cultures, These data provide strong evidenc e that regulation of expression of mdr genes in liver cells in respons e to carcinogens such as 2-AAF is gene- and species-specific.