Publication Details

Category Text Publication
Reference Category Journals
DOI 10.1016/j.jhepr.2023.100930
Licence creative commons licence
Title (Primary) Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism
Author Huillet, M.; Lasserre, F.; Gratacap, M.-P.; Engelmann, B.; Bruse, J.; Polizzi, A.; Fougeray, T.; Martin, C.M.P.; Rives, C.; Fougerat, A.; Naylies, C.; Lippi, Y.; Garcia, G.; Rousseau-Bacquie, E.; Canlet, C.; Debrauwer, L.; Rolle-Kampczyk, U.; von Bergen, M.; Payrastre, B.; Boutet-Robinet, E.; Gamet-Payrastre, L.; Guillou, H.; Loiseau, N.; Ellero-Simatos, S.
Source Titel JHEP Reports
Year 2024
Department MOLTOX
Volume 6
Issue 1
Page From art. 100930
Language englisch
Topic T9 Healthy Planet
Keywords Sexual dimorphism; Hepatic xenobiotic metabolism; Lipoprotein metabolism; Platelet aggregation; Trimethylamine-N-oxide

Background & Aims

The constitutive androstane receptor (CAR) is a nuclear receptor that binds diverse xenobiotics and whose activation leads to the modulation of the expression of target genes involved in xenobiotic detoxification and energy metabolism. Although CAR hepatic activity is considered to be higher in women than in men, its sex-dependent response to an acute pharmacological activation has seldom been investigated.


The hepatic transcriptome, plasma markers, and hepatic metabolome, were analysed in Car+/+ and Car-/- male and female mice treated either with the CAR-specific agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or with vehicle.


Although 90% of TCPOBOP-sensitive genes were modulated in a sex-independent manner, the remaining 10% showed almost exclusive female liver specificity. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation, and extracellular matrix organisation. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Hepatic expression of flavin monooxygenase 3 (Fmo3) was almost abolished and was associated with a decrease in hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a potential role in the control of TMAO homeostasis, CAR activation decreased platelet hyper-responsiveness in female mice supplemented with dietary choline.


More than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic responses such as platelet aggregation. CAR activation may be an important mechanism of sexually-dimorphic drug-induced liver injury.

Impact and implications

CAR is activated by many drugs and pollutants. Its pharmacological activation had a stronger impact on hepatic gene expression and metabolism in females than in males, and had a specific impact on liver toxicity and trimethylamine metabolism. Sexual dimorphism should be considered when testing and/or prescribing xenobiotics known to activate CAR.

Persistent UFZ Identifier
Huillet, M., Lasserre, F., Gratacap, M.-P., Engelmann, B., Bruse, J., Polizzi, A., Fougeray, T., Martin, C.M.P., Rives, C., Fougerat, A., Naylies, C., Lippi, Y., Garcia, G., Rousseau-Bacquie, E., Canlet, C., Debrauwer, L., Rolle-Kampczyk, U., von Bergen, M., Payrastre, B., Boutet-Robinet, E., Gamet-Payrastre, L., Guillou, H., Loiseau, N., Ellero-Simatos, S. (2024):
Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism
JHEP Rep. 6 (1), art. 100930 10.1016/j.jhepr.2023.100930