The sex dimorphic expression of mouse CYP
The sex-dimorphic AS601245 of mouse CYP3A is partially due to sex-dimorphic plasma GH profile which is a decisive factor in the regulation of sexspecific CYP isoforms . Nevertheless, in our study we did not observe any changes in plasma GH levels in either mouse sex with a selective ablation of the GR in the noradrenergic system (Fig. 2). Furthermore, no changes were observed in the level of corticosterone in those animals . The above results suggest the existence of additional mechanisms determined by gender, which are independent of plasma GH and corticosterone levels engaged in the regulation of CYP3A. This suggestion is in line with an observation that the sexually dimorphic pattern of growth hormone secretion is influenced by sex hormones while developmental expression of CYP3A is changed by sexually dimorphic pattern of growth hormone secretion [5, 11]. Thus, the regulatory interplay of sex hormones may play a key role in expression of CYP3A genes.
In addition, we examined the influence of chronic restraint stress on the alteration of CYP3A activity in the liver of mice with a selective ablation of the GR in the noradrenergic system (Figs. 1A and 1B). Indeed, stress is a fight-or-flight response to stressful stimuli that helps an individual to survive. In the present study, mutant mice were more sensitive to chronic restraint stress than were control mice regarding the activity of cytochrome P450 (Figs. 1A and B). The activity of CYP3A was increased by stress in both females and males in mutant mice only. However, the observed increase in enzyme activity was more pronounced in females (up to 153% of the non-stressed mutant level) than in males (up to 136% of the nonstressed mutant level). Interestingly, the level of a stress hormone (corticosterone) increased in both sexes after chronic restraint stress, but there were no differences between mutant and control mice . However, the regulation of the expression of CYP3A is under multi-hormonal control. Thus, it is possible that sex hormones-related factors also play a role after stress exposure. Therefore, further studies are necessary to search for molecular mechanisms responsible for the observed changes in CYP3A activity, and to satisfactorily elucidate the role of the noradrenergic system in the regulation of CYP3A in murine liver. Such an approach seems of particular importance, since sex differences in the CYP-dependent drug metabolism are fairly common in human liver .
Acknowledgments This study was supported by grant No. POIG.01.01.02-12-004/09-00 financed by European Regional Development Fund and by statutory funds from the Institute of Pharmacology, Polish Academy of Sciences, Kraków.
Introduction Viral hepatitis, long-term alcohol consumption, drugs, genetic factors, obesity and nutritional supplements are the leading causes of liver insufficiency and are positively correlated with the altered production of various proinflammatory cytokines, such as TNFα, IL-1, IL-6, and transforming growth factor-β, that act on hepatocytes through Kupffer cells, the resident macrophages of the liver (Morgan, 1997, 2001; Burra et al., 2018). Serotonin present outside the central nervous system is a well-known friend and foe of the liver and has a narrow therapeutic window that determines whether the regenerative process or tumor progression occurs in the liver (Essmann, 1978; Lesurtel et al., 2006, 2012; Mercado et al., 2011; Padickakudy et al., 2017). Moreover, serotonin is involved in the bidirectional communication of the nervous system and immune systems and stimulates macrophage polarization by 5-HT7 and 5-HT2B receptors, the latter of which is detected in vivo in liver Kupffer cells and in tumor-associated macrophages (Young and Matthews, 1995; de las Casas-Engel et al., 2013; D\'Mello and Swain, 2014). In 2013, Svejda at al. reported a functional 5-HT7 receptor in hepatocytes implicated in hepatocyte proliferation (Svejda et al., 2013). Further experiments have shown a role for 5-HT2B as well as 5-HT2A receptors to a lesser extent as mediators of liver insufficiency (Soll et al., 2012; Kot and Daujat-Chavanieu, 2016) that influence the regulation of cytochrome (CYP) 1A isoforms (Kot and Daujat-Chavanieu, 2016).