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Altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms
- Kot, Marta, Daujat-Chavanieu, Martine
- Food and chemical toxicology 2018 v.116 pp. 369-378
- animal models, corticosterone, diet, diethylnitrosamine, interleukin-1beta, interleukin-4, liver, rats, signal transduction, testosterone, toxicology, transforming growth factor beta
- The aim of this study is to assess a potential mechanism by which the serotonergic system can control the expression and activity of cytochrome (CYP) 2C11 and CYP3A isoforms during liver insufficiency.A rat model of diethylnitrosamine (DEN)-induced liver insufficiency was developed by administering 50 mg/kg of DEN twice a week for 7 weeks. Dysfunction of the serotonergic system was evoked by feeding the rats with a tryptophan-free diet for three weeks.Dysfunction of the serotonergic system during liver insufficiency decreased the level of proinflammatory cytokines (TGF-β and IL-1β) and increased the level of an anti-inflammatory cytokine (IL-4). Simultaneously, activation of the repressive mechanism IL-4/JAK1/STAT6/SOCS1 of the JAK2/STAT5b-mediated signal transduction pathway and the pERK1/2/GR/STAT6 signal transduction pathway resulted in the suppression of the CYP2C11 and CYP3A isoforms. Moreover, dysfunction of the serotonergic system during liver insufficiency equalized the level of testosterone to the basal level, did not change the steady state of the corticosterone level and significantly enhanced the reduced level of growth hormone.An altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms during liver insufficiency through mechanisms based on posttranscriptional and posttranslational processes.