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.

Regulation of Sulfotransferase Enzymes by Prototypical Microsomal Enzyme Inducers in Mice

“…It was previously shown that the basal expression of CAR is higher in female than male mice (Kawamoto et al, 2000). Furthermore, the CAR activator (TCPOBOP) resulted in higher induction of the mRNA expression of Cyp2B10 (CAR target gene) in female than male rats (Ledda-Columbano et al, 2003). This might explain the finding in this article that CAR activators do not appear to be strong inducers of Sults, especially in male mice, but are better inducers of Sults in female mice.…”

Importance of Hepatic Induction of Constitutive Androstane Receptor and Other Transcription Factors That Regulate Xenobiotic Metabolism and Transport

“…A gender difference in mouse hepatic CAR expression has been noted previously (Kawamoto et al, 2000;Ledda-Columbano et al, 2003). Furthermore, basal and inducible expression of Cyp2b10 mRNA in female liver is greater than that observed in males (Honkakoski et al, 1992;Ledda-Columbano et al, 2003).…”

Inducibility of Drug-Metabolizing Enzymes by Xenobiotics in Mice with Liver-Specific Knockout ofCtnnb1

“…Due to limited availability of animals, most inducers were tested with either males or females. Induction of CAR-dependent gene expression by the differentially acting CAR agonists TCPOBOP and phenobarbital was studied with mice from both genders, because gender differences in response to CAR agonists have been reported in the literature (Ledda-Columbano et al, 2003). Livers were isolated, and hepatic levels and zonation of various mRNAs and proteins were analyzed.…”