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  • In the present study the expression of the CYP C

    2019-08-13

    In the present study, the clofibrate powder 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). Extending this mechanism, the increased testosterone level observed in response to serotonergic system dysfunction during liver insufficiency led to decreased levels of proinflammatory cytokines. A previous study showed that both physiological and supraphysiological concentrations of testosterone reduce the expression of IL-1β (Corcoran et al., 2010). Moreover, simultaneous increase in the levels of testosterone, serum serotonin, anti-inflammatory IL-4, and STAT6 protein in the nuclear fraction of the liver after serotonergic system dysregulation during liver insufficiency suggests the presence of a testosterone - IL-4 - STAT6 interlink under control of the serotonergic system during liver insufficiency. Consistent with this proposed interlink, one role of PKA is to inhibit the production of the anti-inflammatory cytokine IL-4 (Zhou et al., 2007). In addition, the activated JAK/STAT6 signaling pathway represents the main mediator of IL-4 signaling (Nelms et al., 1999; Nappo et al., 2017), and significant levels of activated STAT6 are observed in primary prostate tissue (Ni et al., 2002), which are controlled by the serum testosterone level (Izumi et al., 2017). Notably, liver failure reduces GnRH secretion by the hypothalamus and leads to secondary testicular failure (Mowat et al., 1976). Moreover, hypophysectomy in male rats decreases CYP2C11 expression to 25 to 30% (Waxman and Holloway, 2009). In contrast, the CYP3A2 isoform is not downregulated by hypophysectomy (Waxman and Holloway, 2009; Li et al., 2015).