2.2.2. Epigenetic mechanisms
2.2.2.1. DNA methylation
DNA methyltransferases add a methyl group to the C5 position of the
cytosine ring of a CpG dinucleotide through a process known as DNA
methylation. Some CYP enzymes include essential CpG islands, therefore,
DNA methylation may be a crucial factor in controlling the production of
some CYP enzymes. Dannenberg et al. inhibited HepG2 cells with the
methyltransferase inhibitor 5-aza-2’-deoxycytidine (5-aza-dC) and found
that the expression of CYP3A4, CYP3A5, CYP3A7, CYP17A1, and CYP19A1 was
affected (Dannenberg et al, 2006). The differences in CYP2E1 expression
between the sexes and months of age were also due to DNA methylation
(Kronfol et al., 2020; Penaloza et al., 2020). In addition, more than 20
CYPs, including CYP1A2, CYP2A6, CYP2C9, and CYP2C19, have been reported
to be regulated by DNA methylation (Jiang et al., 2021; Lkhagvadorj et
al., 2020; Sukmawan et al., 2021). DNA methylation also plays a critical
role in the response to hypoxia. Lin et al. found that differentially
methylated genes were enriched around genes at high altitudes between
Tibetan and non-Tibetan ethnic groups, suggesting that changes in DNA
methylation play a role in acclimatization to high altitudes (Lin et
al., 2023). Zhang and Ruhr et al. showed that DNA methylation under
hypoxia is associated with improved learning memory and enhanced hypoxia
tolerance (Ruhr et al., 2021; Zhang et al., 2023). Methylation of the
CYP promoter during hypoxia also plays an important role in the
adaptation to hypoxia. Jin et al. performed methylation analysis in
Chinese patients with high-altitude pulmonary edema (HAPE) and found
that several CpG sites in the promoter region of the CYP2S1 gene
of were aberrantly methylated (Jin et al., 2022); however, more research
is needed to determine whether DNA methylation also regulates the
expression of other CYP under hypoxic conditions.
2.2.2.2. miRNAs
miRNAs are the most widely studied non-coding RNAs. Hypoxia can
upregulate or downregulate miRNAs expression, while some studies have
indicated that miR-203a-3p expression is downregulated in rat
lung tissues after 24, 48, and 72 h of exposure to 6,000 m altitude (Cai
et al., 2020). Chen et al. found contrasting findings: the levels ofmiR-23a in rats increased after exposure to an altitude of 6,100
mm for either 3 or 7 days, but decreased after 21 days of exposure (Chen
et al., 2017), indicating that hypoxia has a substantial regulatory
effect on miRNA. While miRNAs negatively regulate CYP expression,
Krkoška et al. found that miR-653 and miR-29c are potent
inhibitors of CYP1A2 expression in human hepatic HepaRG cells (Krkoška
et al., 2022). Tantawy et al. discovered a substantial association
between the expression of multiple CYPs and miR-107 using
genome-wide miRNA analysis (Tantawy et al., 2022). Additionally, miRNAs
negatively regulate the expression of CYP2C8, CYP2C9, and CYP2E1 (Kugler
et al., 2020; Matthews et al., 2020). Hypoxia can upregulate or
downregulate the expression of miRNAs, which, in turn, regulate CYPs,
suggesting that miRNAs are the key molecular mechanisms by which hypoxia
affects the expression of CYPs. In our study, we found thatmiR-873-5p expression was substantially reduced in Caco-2 cells
after 24 h of incubation in 2% O2, regulated the
expression of MDR1 and PXR, and mediated changes in the function and
expression levels of drug transporters under hypoxia (Duan et al.,
2022). It would be worthwhile to further investigate whether miRNAs have
the same effects on the function and expression of CYP. Moreover, long
noncoding RNAs (lncRNAs) play a role in controlling CYP expression and
are affected by hypoxia (Lu et al., 2021; Wang et al., 2020). We
hypothesized that lncRNAs play comparable roles in regulating the
activity and expression of CYP genes under hypoxic conditions. Further
research is required to elucidate this relationship.
2.2.2.3. Histone modifications
Histone modification is the process of extending the amino termini of
core histones from the globular region of the nucleosome for
modifications. Histone modifications also regulate the expression of
CYPs. Velenosi et al. found that reduced nuclear receptor binding and
histone acetylation promote the reduced expression of CYP2C and CYP3A in
chronic kidney disease (Velenosi et al., 2014). Romidepsin (FK228), a
selective inhibitor of histone deacetylase 1 (HDAC1) and HDAC2, showed a
reduction in the extent of renal injury, a substantial reduction in
CYP2E1, an upregulation of H3 acetylation, and a substantial increase in
the binding of HNF-1α to the CYP2E1 promoter after treatment with FK228
in a mouse model of acute kidney injury (Cheng et al., 2020). Histone
modifications also affect the expression of CYP3A4 and CYP2C9 (Jiang et
al., 2021; Yan et al., 2017). Hypoxia leads to unique chromatin
modifications that affect the activity and expression of histone
demethylases. Changes in the expression and function of CYP under
hypoxic conditions may be linked to chromatin reprogramming. Kassie et
al. observed changes in the levels of certain proteins in the lungs of
tumor-bearing mice, revealing that CYP2B10 and CYP2F2 were downregulated
in tumor tissues, whereas histone expression was upregulated (Kassie et
al., 2008). While the current evidence is insufficient to fully
elucidate the role of histone modifications in regulating CYP expression
during hypoxia, it has been suggested that histone-modifying enzymes
control hypoxia-inducible factor (HIF) expression during hypoxia. In
turn, HIF is associated with changes in CYP levels. This connection may
be a promising area for future research on the regulation of CYP
expression via histone modification during hypoxia.