Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism.

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.

Methods

The hepatic transcriptome, plasma markers, and hepatic metabolome, were analysed in

Results

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

Conclusions

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.

Informations de copyright

© 2023 The Authors.

Déclaration de conflit d'intérêts

The authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details.