Cytochrome P450 genes are differentially expressed in female and male hepatocyte retinoid X receptor alpha-deficient mice.
To study the functional role of retinoid X receptor alpha (RXRalpha) in hepatocytes, hepatocyte RXRalpha-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 RXRalpha-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 17beta-estradiol and 5alpha-dihydrotestosterone (DHT) treatment, respectively, and then the expression of the CYP450 genes was studied. Estradiol had no effect on protecting the hepatocyte RXRalpha-deficient mice from reduced expression of the CYP450 genes. In contrast, DHT induced hepatocyte RXRalpha-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 RXRalpha-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 RXRalpha is low, which may in turn reduce the expression of the CYP450 genes.
Department of Pathology, University of Rochester, Rochester, New York 14642, USA.
Yan
Y
Cai
Tiane
T
Dai
Yan
Y
Ao
Tamiko
T
Konishi
Kuang-Hsiang
KH
Chuang
Yanhe
Y
Lue
Chawnshang
C
Chang
Yu-Jui Yvonne
YJ
Wan
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000737:chemistry / Q000502:physiology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009919:Orchiectomy; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D010641:Phenotype; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000235:genetics*; D047488:Retinoid X Receptors; D012727:Sex Characteristics; D013739:Testosterone / Q000502:physiology; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D012333:RNA, Messenger; D011944:Receptors, Androgen; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D013196:Dihydrotestosterone; D013739:Testosterone; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D042926:Cytochrome P-450 CYP4A; D010089:Oxidoreductases, N-Demethylating