title: Sex difference in the proliferative response of mouse hepatocytes to treatment with the CAR ligand, TCPOBOP.
abstract: The nuclear receptor Constitutive Androstane Receptor (CAR) binds DNA as a heterodimer with the retinoic-X receptor and activates gene transcription. Previously, in vitro studies have shown that the testosterone metabolites, androstenol and androstenol, inhibit the constitutive transcriptional activity of CAR, suggesting that differences might exist in the response to CAR-mediated gene activation between different sexes. In this study, we have analyzed the response of female and male CD-1 mice to stimulation of hepatocyte proliferation caused by the CAR ligand TCPOBOP. Results showed that the labelling index of female hepatocytes at 24, 30 and 36 h after treatment was much higher than that found in males. The higher proliferative activity of female hepatocytes was associated with increased hepatic levels of cyclin D1, cyclin A, E2F and enhanced phosphorylation of pRb and p107. The increased mitogenic response of females was associated with higher mRNA levels of CYP2B10, a known target of CAR. Administration of androstenol to TCPOBOP-treated mice caused a reduction of labelling index, which was accompanied by a decrease of CYP2B10 and CAR mRNA levels. In conclusion, the results show that, in addition to microsomal detoxification, another biological response elicited by the CAR ligand TCPOBOP, namely, hepatocyte proliferation, occurs at higher levels in female than male mice, suggesting that CAR transcriptional activity in males is partially counteracted by physiological higher levels of testosterone metabolites such as androstenol and androstenol.
authors.affiliation: Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy.
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Ledda-Columbano
authors.forename: Monica
authors.initials: M
authors.lastname: Pibiri
authors.forename: Danilo
authors.initials: D
authors.lastname: Concas
authors.forename: Francesca
authors.initials: F
authors.lastname: Molotzu
authors.forename: Gabriella
authors.initials: G
authors.lastname: Simbula
authors.forename: Costanza
authors.initials: C
authors.lastname: Cossu
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
mesh_terms: D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D019938:Cyclin D1 / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D012727:Sex Characteristics; D013250:Steroid Hydroxylases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D000732:Androstanols; D000090702:Constitutive Androstane Receptor; D011725:Pyridines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019938:Cyclin D1; C000658:androstan-3-ol; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2