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The overexpression of P-glycoprotein (Pgp) appears to be responsible for multidrug resistance in some human cancers. The molecular basis of this overexpression is not understood. We have used primary monolayer cultures of adult rat hepatocytes as a model system to study the regulation of Pgp gene expression (Lee et al., J. Cell. Physiol., 157: 392-402, 1993). We observed a dramatic and specific overexpression of class II Pgp as a function of the time in culture. This isoform of Pgp, which is expressed at a very low level in normal liver, has also been shown to be predominantly overexpressed in several models of rat liver carcinogenesis. In the present study, we have used nuclear run-on assays and mRNA decay studies to investigate the mechanism for the overexpression of class II Pgp in cultured hepatocytes. We conclude that an increased mRNA stability is the major factor involved in the increased …