Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) are responsible for cystic fibrosis. The CFTR gene has recently been identified and encodes a 6.5-kb mRNA transcript. Recent observations showing that CFTR expression increases during differentiation of epithelial cells suggested that CFTR may also be regulated in the liver in response to partial hepatectomy (PH). We studied the expression of CFTR in rat regenerating liver and investigated the mechanisms that regulate CFTR RNA levels during a 120-h period after PH. Northern and slot-blot analysis revealed a liver-specific biphasic increase of CFTR mRNA levels, which peaks at 2 and 24 h post-PH. In contrast to these findings, the mode of regulation of the homologous gene MDR-1 showed a clearly different pattern. Nuclear run-on analysis demonstrated increased levels of CFTR transcription corresponding to the time points where an increase in CFTR message was observed. Similarly, the beta-actin gene, which increases transiently during liver regeneration, showed increased nuclear run-on activity 4 h posthepatectomy, indicating that the nuclei were functional. No increase of MDR-1 gene transcription was detected, confirming the previous finding that the increase in MDR-1 mRNA level in regenerating liver results from a post-transcriptional event such as message stabilization. This study indicates that expression of the CFTR gene is regulated during the regenerative process of the liver. The data also suggest that the increase in CFTR and MDR expression levels result from two distinct regulatory mechanisms.