title: The impact of serotonergic system dysfunction on the regulation of P4501A isoforms during liver insufficiency and consequences for thyroid hormone homeostasis.
abstract: 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.
authors: Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland. Electronic address: kot@if-pan.krakow.pl.
authors: Marta
authors: M
authors: Kot
authors: Institute for Regenerative Medicine and Biotherapy, Hôpital St Eloi, CHU, Montpellier, France; INSERM, U1183, Université Montpellier, UMR 1183, IRMB, Hôpital St Eloi, 34295 Montpellier, France.
authors: Martine
authors: M
authors: Daujat-Chavanieu
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D048550:Hepatic Insufficiency / Q000139:chemically induced / Q000378:metabolism*; D006706:Homeostasis; D051381:Rats; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
chemical_list: D000477:Alkylating Agents; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D004052:Diethylnitrosamine; D014453:Glucuronosyltransferase; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme
keywords: AhR; CYP1A isoforms; Liver; Metabolism; Serotonin; Thyroid hormones