Cytochrome P450 genes are differentially expressed in female and male hepatocyte retinoid X receptor α-deficient mice

Abstract

To study the functional role of retinoid X receptor α (RXRα) in hepatocytes, hepatocyte RXRα-deficient mice have been established. Characterization has been performed on male mice. In this paper, we show that the expression of CYP450 genes is differentially expressed in male and female hepatocyte RXRα-deficient mice; male mice have reduced expression of cytochrome P450 (CYP) CYP4A, CYP3A, and CYP2B mRNAs, but females do not exhibit such phenotypes. To examine the hormonal effects on this sexual dimorphic phenotype, male and female mice were subjected to 17β-estradiol and 5α-dihydrotestosterone (DHT) treatment, respectively, and then the expression of the CYP450 genes was studied. Estradiol had no effect on protecting the hepatocyte RXRα-deficient mice from reduced expression of the CYP450 genes. In contrast, DHT induced hepatocyte RXRα-deficient female mice, but not wild-type female mice, to have the reduced expression of CYP450 mRNAs. In addition, castration prevented the mutant male mice from exhibiting reduced expression of CYP450 mRNAs. wild-type and mutant mouse livers from both genders express androgen receptors (ARs). By transient transfection, DHT-AR could inhibit RXRα-mediated transcription. Furthermore, by transfection and coimmunoprecipitation, RXR can interact with AR in vivo. These data suggest that testosterone has a negative impact on retinoid signaling when the level of RXRα is low, which may in turn reduce the expression of the CYP450 genes.