2.2.3. Cytokines
2.2.3.1 Inflammatory factor
In some models of inflammation or infection, CYP protein and mRNA levels are reduced (Morgan, 2009; Morgan et al., 2002). Inflammatory factors, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) affect CYP expression and activity (Dunvald et al., 2022). In addition, the downregulation of CYP has been associated with increased expression of nuclear factor (NF)-κB (Yu et al., 2017). Systemic inflammation caused by acute and chronic diseases involves a complex mechanism for altering CYP under hypoxic conditions. Fradette et al. discovered that acute moderate hypoxia caused a reduction in the activity and expression of CYP1A1 and CYP1A2, while increasing the activity and expression of CYP3A6. These changes in CYPs were attributed to the production of interferon-gamma (IFN-γ), IL-1β, IL-2, and other factors (Fradette et al., 2002). A separate investigation yielded comparable findings, indicating that exposure to low oxygen levels notably decreased hepatic CYP1A mRNA and protein levels in fish living under normal oxygen conditions. Hypoxia substantially increased the levels of IL-1b and HIF-2a mRNA, and endothelial NOS proteins. These findings indicated that the decrease in CYP levels caused by hypoxia was a result of changes in the levels of inflammatory factors and HIF (Rahman et al, 2012; Shi et al., 2017).
2.2.3.2 HIF
HIF is a key regulator of the hypoxic response in the body, and it regulates the expression of several downstream target genes and is involved in the regulation of CYP expression. Under normal oxygen conditions, the proline hydroxylase (PHD) enzyme becomes active, leading to the breakdown of HIF-1 by proteases. In the presence of hypoxia, the activity of the PHD is suppressed, leading to the stabilization of HIF-1. This stabilization of HIF-1 triggers the upregulation of CYP expression, which in turn facilitates adaptation to hypoxic conditions. Liu et al. cultured astrocytes under hypoxic conditions for 1, 3, and 6 h and observed a substantial increase in CYP2C11 mRNA and protein levels. The increase in HIF-1α protein preceded the increase in CYP2C11 expression after 1 h of hypoxia, and a specific direct interaction between the CYP2C11 promoter DNA and HIF-1α was also found, which in turn upregulated the induction of astrocyte tolerance (Liu et al, 2005). Ramakrishnan et al. found that the activation of HIF signaling under hypoxia resulted in increased expression of the CYP7A1 negative regulator E4BP4, which inhibits bile acid synthesis, leading to an adaptive increase in cholesterol levels (Ramakrishnan et al., 2014). In addition, HIF has been associated with the downregulation ofCYP1A2 , CYP2B6 , CYP3A4 , CYP3A6 ,CYP2J2 , and CYP4BQ (Fradette et al, 2003; Mastyugin et al., 2004; Rivera et al., 2007; Takano et al., 2021).