EXPRESSION OF MULTIDRUG-RESISTANCE GENES IN RAT-LIVER DURING REGENERATION AND AFTER CARBON-TETRACHLORIDE INTOXICATION

We analyzed expression of multidrug resistance (mdr) genes in rat live r during regeneration after partial hepatectomy or carbon tetrachlorid e-induced necrosis. In situ hybridization revealed that in the normal liver the cellular distribution of mdr transcripts and protein is rest ricted to hepatocytes and that a gradient, highest in zone 1 and lowes t in zone 3, exists in the level of the mdr transcripts in the liver a cinus. Increased levels of mdr1a and mdr1b transcripts were observed 3 hr after administration of carbon tetrachloride and remained increase d for the next 5 days. In contrast, increased expression of mdr1a and mdr1b was first observed 24 hr after partial hepatectomy. Use of gene- specific probes to compare the time courses of mdr1b and mdr2 expressi on after carbon tetrachloride administration showed distinctly differe nt patterns of expression; mdr1b reached a maximum level of expression at 12 hr, whereas increased mdr2 expression was first observed 48 hr after administration. Nuclear run-on analysis at 12 and 24 hr after ca rbon tetrachloride administration demonstrated 10-fold and eightfold i ncreases in mdr transcription, respectively. However, 72 hr after carb on tetrachloride treatment the rate of mdr transcription was back to t he control level. The cellular patterns of mdr expression after partia l hepatectomy and carbon tetrachloride administration were similar; th e increase was first observed in zone 1 and gradually extended into zo ne 3. These data strongly suggest that the physiological roles of mdr1 b and mdr2 are different and that liver regeneration is an appropriate model for elucidating these differences.