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  • In the present study the expression of the

    2020-07-30

    In the present study, the methysergide of the CYP2C11 gene and the levels of its protein and activity were decreased in rats with liver insufficiency and in rats after induced dysfunction of the serotonergic system during normal liver function. Moreover, serotonergic system dysfunction during liver insufficiency significantly enhanced the reduced expression of the CYP2C11 gene and the levels of its protein and activity, suggesting the initiation of a new mechanism that reduces the expression of this CYP isoform. Activation of the JAK2/STAT5b signaling pathway by growth hormones, which is a well-known signaling pathway that regulates the levels of the CYP2C11 isoform, increases the expression of the CYP2C11 gene (Choi and Waxman, 2000a, 2000b). However, the sequences that are important for CYP2C11 downregulation by cytokine are located within the proximal region of the CYP2C11 gene, and the expression of CYP2C11 mRNA can be rapidly suppressed by IL-1β (Wright and Morgan, 1990; Chen et al., 1995; Sewer and Morgan, 1998). Decreased growth hormone levels and increased IL-1β levels confirm the key role of IL-1β in the regulation of CYP2C11 in rats with liver insufficiency and in rats after induced dysfunction of the serotonergic system during normal liver function. Nonetheless, the discrepancy in the level of the CYP2C11 protein during liver insufficiency and after dysfunction of the serotonergic system during normal liver function indicates the different molecular mechanisms underlying this suppression of the CYP2C11 isoform. Moreover, the CYP2C11 protein detected after dysfunction of the serotonergic system during normal liver function suggests the presence of a protective mechanism under control of the serotonergic system that blocks CYP2C11 degradation, which will be a subject of our future study. Furthermore, dysfunction of the serotonergic system during liver insufficiency led to a decreased level of IL-1β and downregulation of IGF-1, a target gene of STAT5b, suggesting an interaction between the IL-1β-dependent and STAT5b-dependent signaling pathways under control of the serotonergic system. The observed decrease in the protein level of JAK2 and the concomitant increase in the protein levels of JAK1, STAT6 and SOCS1 after dysfunction of the serotonergic system during liver insufficiency confirmed the activation of negative regulators of the JAK2/STAT5b-mediated signal transduction pathway. Therefore, dysfunction of the serotonergic system during liver insufficiency activates the JAK1/STAT6/SOCS-1 signal transduction pathway, which leads to suppression of the CYP2C11 isoform. Consistent with this conclusion, previous studies have shown that SOCS-1 participates in a negative feedback loop to suppress JAK/STAT signaling and enhance proteasome-dependent degradation of JAK2 (Endo et al., 1997; Ungureanu et al., 2002). Moreover, the unstimulated JAK2 protein has a relatively short half-life, which is considered a regulatory mechanism during cytokine-dependent signaling (Siewert et al., 1999). Notably, SOCS-1 is an antioncogene that prevents carcinogenesis by suppressing chronic inflammation. In addition, SOCS-1+/-  mice are hypersensitive to dimethylnitrosamine-induced hepatocarcinogenesis (Yoshida et al., 2004; Yoshimura et al., 2007).