The impact of serotonergic system dysfunction on the regulation of P4501A isoforms during liver insufficiency and consequences for thyroid hormone homeostasis

• The peripheral serotonergic system plays a significant role in molecular events promoting activation of the AhR receptor.
• Dysfunction of the serotonergic system during liver insufficiency generates the “superinduction” of the AhR target genes.
• The activation of PKC appears during liver insufficiency with serotonergic system dysfunction.
• The regulation of CYP1A subfamily is dependent on hepatic function under control of the serotonergic system.
• The AhR target genes induction can be observed without influence from thyroid hormones.

This study aimed to evaluate the impact of serotonergic system dysfunction on the regulation of cytochrome P4501A (CYP1A) during liver insufficiency. A rat model of liver insufficiency with a dysfunctional serotonergic system was developed. To induce liver insufficiency, animals were treated with nitrosodiethylamine (DEN) at 50 mg/kg of body weight twice a week for 7 weeks. To induce serotonergic system dysfunction, the animals were fed a tryptophan-free diet for 3 days.Serotonergic system dysfunction during liver insufficiency generated the aryl hydrocarbon receptor (AhR) activation and the “superinduction” of the AhR target genes: CYP1A1, CYP1B1 and UGT1A, with a concomitant increase in CYP1A1 protein and activity. CYP1A2 gene expression was simultaneously down-regulated, with a concomitant decrease in CYP1A2 protein and activity. A significant reduction in TRβ receptor levels, together with a simultaneous increase of TRα receptor gene and protein level (mainly TRα2 isoform) after serotonergic system dysfunction, suggests that the serotoninergic system is involved in the regulation of CYP1A isoforms without influence from thyroid hormones during liver insufficiency.The interplay between the serotonergic system and the regulation of CYP1A isoforms, which are downstream targets of AhR activation, is dependent on hepatic function and can be observed without influence from thyroid hormones.

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