Overexpression of P-glycoprotein in rat hepatocellular carcinomas induced with N-nitrosomorpholine.

The most frequently reported alteration of multidrug resistance (MDR) is the overexpression of the 170 kd membrane glycoprotein. An increased expression of the MDR-gene in pre-neoplastic and neoplastic liver lesions produced experimentally by different carcinogens has been reported. As shown in rat liver by stop experiments, specific carcinogen-induced alterations can be separated from non-specific, toxic changes. Therefore, we induced rat hepatocellular carcinomas with N-nitrosomorpholine and investigated whether expression of the MDR-gene also takes place in hepatocellular carcinomas after withdrawal of the carcinogen. Using mAb C219 against P-glycoprotein, both normal liver and hepatocellular carcinomas show specific immunoreactivity by means of immunofluorescence and immunohistochemistry. In hepatocellular carcinomas, however, the reaction is increased if compared to normal liver of untreated control animals. These results were confirmed by immunoblotting. Using the cDNA probe 1.5, a significant increase in MDR-gene transcripts was found in hepatocellular carcinomas as compared to normal liver.