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.