We analyzed expression of multidrug resistance (mdr) genes in rat liver during regeneration after partial hepatectomy or carbon tetrachloride-induced necrosis. In situ hybridization revealed that in the normal liver the cellular distribution of mdr transcripts and protein is restricted to hepatocytes and that a gradient, highest in zone 1 and lowest in zone 3, exists in the level of the mdr transcripts in the liver acinus. Increased levels of mdrla and mdrlb transcripts were observed 3 hr after administration of carbon tetrachloride and remained increased for the next 5 days. In contrast, increased expression ofmdrla and mdrlb was first observed 24 hr after partial hepatectomy. Use of gene-specific probes to compare the time courses of mdrlb and mdr2 expression after carbon tetrachloride administration showed distinctly different patterns of expression; mdrlb 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 carbon tetrachloride administration demonstrated 10-fold and eightfold increases in mdr transcription, respectively. However, 72 hr after carbon tetrachloride treatment the rate of mdr transcription was back to the control level. The cellular patterns of mdr expression after partial hepatectomy and carbon tetrachloride administration were similar; the increase was first observed in zone 1 and gradually extended into zone 3. These data strongly suggest that the physiological roles of mdrlb andmdr2 are different and that liver regeneration is an appropriate model for elucidating these differences. (HEPATOLOGY 1993; 18: 1202-1207.) Multidrug resistance is the phenomenon in which cells exposed to one drug become resistant to that agent and to a range of structurally and functionally unrelated compounds (1-3). One well-characterized mechanism by which cells become resistant is increased expression of a