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Cytochrome P450 Genes Are Differentially Expressed in Female and Male Hepatocyte Retinoid X Receptor -Deficient Mice

Department of Pathology (K.-H.C., C.C.), University of Rochester, Rochester, New York 14642; and Departments of Pathology (Y.C., T.D., Y.A., T.K., Y.-J.Y.W.) and Medicine (Y.L.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90509

Address all correspondence and requests for reprints to: Yu-Jui Yvonne Wan, Ph.D., Department of Pathology, Harbor-University of California, Los Angeles Medical Center, 1000 West Carson Street, Torrance, California 90509. E-mail: agarose{at}ucla.edu.

To study the functional role of retinoid X receptor (RXR) in hepatocytes, hepatocyte RXR-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 RXR-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 17ß-estradiol and 5-dihydrotestosterone (DHT) treatment, respectively, and then the expression of the CYP450 genes was studied. Estradiol had no effect on protecting the hepatocyte RXR-deficient mice from reduced expression of the CYP450 genes. In contrast, DHT induced hepatocyte RXR-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 RXR-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 RXR is low, which may in turn reduce the expression of the CYP450 genes.

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