ACTIVATION OF DISTINCT MULTIDRUG-RESISTANCE (P-GLYCOPROTEIN) GENES DURING RAT-LIVER REGENERATION AND HEPATOCARCINOGENESIS

The multidrug transporter P-glycoproteins are encoded by three multidr ug-resistance (mdr) genes in rodents, designated mdr1a (mdr3), mdr1b ( mdr1), and mdr2. Only the first two genes are functionally related to multidrug resistance. Activation of rodent mdr genes during liver rege neration and hepatocarcinogenesis has been reported. In mice, mdr1a is activated in hepatocellular carcinomas (HCCs) produced by various car cinogenic protocols, whereas both mdr1a and mdr2 are activated during liver regeneration. In this communication, we report isolating three g ene-specific probes for the rat mdr homologues, which were used as pro bes in an RNase protection assay to demonstrate that mdr1b mRNA was ex pressed in HCCs induced by two different protocols. Furthermore, high levels of hepatic mdr1b mRNA but only moderate levels of mdr1a and mdr 2 mRNA were seen in preneoplastic lesions in rats treated with 2-acety laminofluorene. Likewise, highly elevated levels of hepatic mdr1b mRNA but only moderately increased levels of mdr1a and mdr2 mRNA were seen after partial hepatectomy. Nevertheless, the general patterns of tiss ue-specific expression of these three mdr genes were similar in rats a nd mice. These results reveal a complex hepatic gene expression patter n during hepatocarcinogenesis and hepatic proliferation for this conse rved gene family in rodents. (C) 1993 Wiley-Liss, Inc.