Huillet Marine, Lasserre Frédéric, Gratacap Marie-Pierre, Engelmann Beatrice, Bruse Justine, Polizzi Arnaud, Fougeray Tiffany, Martin Céline Marie Pauline, Rives Clémence, Fougerat Anne, Naylies Claire, Lippi Yannick, Garcia Géraldine, Rousseau-Bacquie Elodie, Canlet Cécile, Debrauwer Laurent, Rolle-Kampczyk Ulrike, von Bergen Martin, Payrastre Bernard, Boutet-Robinet Elisa, Gamet-Payrastre Laurence, Guillou Hervé, Loiseau Nicolas, Ellero-Simatos Sandrine
Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France.
INSERM, UMR-1297 and Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), CHU-Rangueil, Toulouse, France.
JHEP Rep. 2023 Oct 13;6(1):100930. doi: 10.1016/j.jhepr.2023.100930. eCollection 2024 Jan.
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 and 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 -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 () 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.
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.
组成型雄烷受体（CAR）是一种核受体，可结合多种外源性物质，其激活会导致参与外源性物质解毒和能量代谢的靶基因表达发生调节。尽管人们认为CAR在肝脏中的活性女性高于男性，但其对急性药物激活的性别依赖性反应很少被研究。
对用CAR特异性激动剂1,4-双[2-(3,5-二氯吡啶氧基)]苯（TCPOBOP）或赋形剂处理的雄性和雌性小鼠进行肝脏转录组、血浆标志物和肝脏代谢组分析。
虽然90%的对TCPOBOP敏感的基因以性别无关的方式被调节，但其余10%几乎只在雌性肝脏中具有特异性。这些雌性特异性的对TCPOBOP敏感的基因主要参与外源性物质代谢、炎症和细胞外基质组织。与雄性相比，CAR激活在雌性中还诱导了更高的肝脏氧化应激和肝细胞溶解。在经TCPOBOP处理的雌性小鼠中，黄素单加氧酶3（FMO3）的肝脏表达几乎被消除，并且与肝脏三甲胺-N-氧化物（TMAO）浓度降低有关。与在TMAO稳态控制中的潜在作用一致，CAR激活降低了补充膳食胆碱的雌性小鼠的血小板高反应性。
超过10%的对CAR敏感的基因具有性别特异性，并影响肝脏和全身反应，如血小板聚集。CAR激活可能是药物性肝损伤性别差异的重要机制。
CAR被许多药物和污染物激活。其药理激活对雌性肝脏基因表达和代谢的影响比对雄性更强，并且对肝脏毒性和三甲胺代谢有特定影响。在测试和/或开具有已知可激活CAR的外源性物质时，应考虑性别差异。
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