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).