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Klyushova, L.S.;  Perepechaeva, M.L.;  Grishanova, A.Y. CYP3A in Health and Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/34176 (accessed on 03 December 2023).
Klyushova LS,  Perepechaeva ML,  Grishanova AY. CYP3A in Health and Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/34176. Accessed December 03, 2023.
Klyushova, Lyubov S., Maria L. Perepechaeva, Alevtina Y. Grishanova. "CYP3A in Health and Disease" Encyclopedia, https://encyclopedia.pub/entry/34176 (accessed December 03, 2023).
Klyushova, L.S.,  Perepechaeva, M.L., & Grishanova, A.Y.(2022, November 11). CYP3A in Health and Disease. In Encyclopedia. https://encyclopedia.pub/entry/34176
Klyushova, Lyubov S., et al. "CYP3A in Health and Disease." Encyclopedia. Web. 11 November, 2022.
CYP3A in Health and Disease
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10112686

CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43. CYP3A enzymes are indiscriminate toward substrates and are unique in that these enzymes metabolize both endogenous compounds and diverse xenobiotics. Constitutive regulation of CYP3A4 transcription, both positive and negative, is mediated by hepatocyte nuclear factor 4α (HNF4α) and other hepatic transcription factors. CYP3A4 expression is modulated by various mechanisms involving nuclear receptors, hormones, xenobiotics, and signaling molecules. CYP3A4 is regulated by a large number of xenobiotics, including many drugs, endogenous compounds, and many hormones, such as triiodothyronine, dexamethasone, and growth hormone. Xenobiotic- and endobiotic-mediated CYP3A4 induction is indirect and entails activation of such ligand-dependent nuclear receptors as PXR, CAR, VDR, glucocorticoid receptor (GR) α, estrogen receptor (ER) α, bile acid receptor (farnesoid X receptor; FXR), oxysterol receptor (liver X receptor; LXR), and peroxisome proliferator-activated receptor alpha (PPARα) as well as by binding to the three major cis-acting modules: CLEM4, distal XREM, and prPXRE.

CYP3A CYP3A regulation CYP3A endogenous substrates drug-metabolizing enzymes

1. Introduction

The CYP3A subfamily is affiliated with the cytochrome P450 (CYP) superfamily, which represents monooxygenases that catalyze the breakdown of various substances via hydroxylation and epoxidation with the participation of an electron donor (NADPH) and molecular oxygen [1]. CYP enzymes function as the first line of defense against exogenous chemical agents [2]. CYP enzymes are responsible for approximately three-quarters of all drug metabolism reactions in the human body [3][4]. CYP enzymes are involved in many critical metabolic reactions, including the metabolism of steroid hormones, bile acids, polyunsaturated fatty acids, leukotrienes, and eicosanoids [3].

Genes of CYP enzymes have been found in the genetic material of representatives of all kingdoms of living organisms, including plants. There are 57 known functional CYP genes in the human genome, aside from 58 pseudogenes whose protein products are enzymes metabolizing a wide range of endogenous and exogenous chemical compounds [2][5][6]. The genes of CYP enzymes are categorized into 18 families and 43 subfamilies based on the percentage of amino acid sequence homology. Just 3 families—CYP2, CYP3, and CYP4—contain more genes than the other 15 families combined [4][7]. The human CYP3 family consists of a single subfamily, CYP3A, which contains four genes (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) encoding four functional enzymes [5][6][8][9][10].

CYP3A is a major subfamily in the cytochrome P450 superfamily. CYP3A enzymes are involved in the metabolism of more than 30% [11] and according to other reports 45–60% [12][13][14] of all pharmaceutical drugs currently on the market. CYP3A enzymes also metabolize some endogenous substrates, including hormones and bile acids, as well as nonpharmaceutical xenobiotics [11][12][13].

Expression of CYP3A enzymes is regulated and varies under the influence of various exogenous (drugs, chemicals, and diets) and endogenous factors (fatty acids, hormones, cytokines, and microRNAs [miRs or miRNAs]) [11].

CYP3A enzymes’ activity can be influenced by anthropogenic environmental chemicals: organophosphates, carbamates, parabens, benzotriazole UV stabilizers, and plasticizers [11][12]. Natural compounds present in foods—e.g., flavonoids found in fruits and vegetables, coffee, tea, chocolate, and wine—can alter CYP3A enzymes’ expression [15]. A prime example is the inhibition of CYP3A enzymes’ expression by components of grapefruit juice [12][16]. There is experimental evidence that retinoids can regulate the expression of CYP3A genes [17]. Certain diets, such as high-fat diets, can alter the expression of CYP3A genes [18], and it is likely that human dietary habits can affect basal expression of these genes [11].

Many of these substances are in turn metabolized by induced CYP3A enzymes, and this feedback mechanism implements detoxification of potentially harmful compounds [12].

2. Mechanisms of CYP3A Regulation

CYP3A4 expression is modulated by various mechanisms involving nuclear receptors, hormones, xenobiotics, and signaling molecules. CYP3A4 is regulated by a large number of xenobiotics, including many drugs, endogenous compounds, and many hormones, such as triiodothyronine, dexamethasone, and growth hormone [19].

Xenobiotic- and endobiotic-mediated CYP3A4 induction is indirect and entails activation of such ligand-dependent nuclear receptors as PXR, CAR, VDR, glucocorticoid receptor (GR) α, estrogen receptor (ER) α, bile acid receptor (farnesoid X receptor; FXR), oxysterol receptor (liver X receptor; LXR), and peroxisome proliferator-activated receptor alpha (PPARα) [10][11][14][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] as well as by binding to the three major cis-acting modules: CLEM4, distal XREM, and prPXRE (Figure 1) [10].

Biomedicines 10 02686 g003

Figure 1. Transcriptional regulation of CYP3A4. Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and vitamin D receptor (VDR) control basal and inducible expression of CYP3A4 through competitive binding to the same set of response elements (everted repeats 6, ER6; direct repeats DR3, and DR4). PXR, CAR, or VDR unbound by a ligand is located in the cytoplasm as a complex with heat shock protein 90 (HSP90) or cytoplasmic constitutive active/androstane receptor retention protein (CCRP). When activated by a ligand, each of them forms a heterodimer with retinoid X receptor α (RXRα), relocates to the nucleus, binds to a response element, recruits coactivators, and activates CYP3A4 transcription. Estrogen receptor (ER) and glucocorticoid receptor (GR) raise CYP3A4 expression by enhancing the expression of CAR, RXRα, and PXR. Ligand-activated farnesoid X receptor (FXR) upregulates small heterodimer partner (SHP), which prevents the recruitment of coactivators to chromatin and/or forms heterodimers with RXRα, thereby inhibiting CYP3A4 expression. Histone deacetylase 1 (HDAC1) inhibition by carbamazepine downregulates CYP3A4. Liver X receptor (LXR) forms a heterodimer with RXRα that then binds to DR4 in the target gene, thus repressing its expression. After the binding of a ligand to LXR or RXR, the heterodimer changes its conformation, which leads to a release of corepressors and the recruitment of coactivators. This event causes transcription of a target gene (peroxisome proliferator-activated receptor alpha; PPARα), its protein product binds as a PPARα–RXRα heterodimer to motifs DR1 and DR2 and enhances the transcription of CYP3A4 and PXR. Ligand-activated PXR suppresses PPARα-dependent gene expression by inhibiting peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) recruitment. Hypoxia and inflammation induce the activity of nuclear factor kappa B (NF-κB) and promote a release of the cytokines that increase the transcription of CCAAT enhancer-binding protein beta (C/EBPβ) and the translation of C/EBPβ-LIP mRNA. C/EBPβ-LIP competes with C/EBPα and C/EBPβ-LAP for binding to response elements in the promoter of CYP3A4, thus lowering its expression. NF-κB activates miR-155, which directly targets mRNAs of suppressors of cytokine signaling proteins (especially suppressor of cytokine signaling 1: SOCS1) thereby inhibiting obligatory negative feedback regulation of inflammatory responses. Abbreviations. C/EBPβ-LAP: a C/EBPβ isoform called liver-enriched activator protein; C/EBPβ-LIP: a C/EBPβ isoform called liver-enriched inhibitory protein; COUP-TFI: chicken ovalbumin upstream promoter transcription factor I; COUP-TFII: chicken ovalbumin upstream promoter transcription factor II; DR1, DR2, DR3, DR4, and ER6: AG(G/T)TCA-like direct repeats separated by 1, 2, 3, or 4 bases, respectively, and an inverted repeat separated by 6 bases; ERE: ER-responsive element; FXRE: FXR-responsive element, GRE: GR-responsive element; HIF-1α: hypoxia-inducible factor 1-α; HNF-4α-AS1: hepatocyte nuclear factor 4α-antisense-RNA 1; IL-2, -4, or -6: interleukin 2, 4 or 6; INFγ: interferon γ; PHD2: prolyl hydroxylase domain-containing protein 2; TNF: tumor necrosis factor; TRα1: thyroid hormone receptor-α1; TRβ1: thyroid hormone receptor-β1.

Thus, most CYP3A inducers act through transcriptional activation [9][11][13]. CYP3A isoforms and nuclear receptors involved in their regulation are subject (as part of post-transcriptional regulation) to ubiquitination (CYP3A4 and CYP3A5) and phosphorylation (CYP3A4 and PXR) [11], whereas post-translational regulation of CYP3A enzymes consists of the stabilization of CYP3A mRNAs and proteins [6][11].

Molecular mechanisms of induction may differ among the four major human CYP3A genes and among their polymorphic variants owing to differences in their structure, and the mechanisms can also differ among different tissues, possibly because of different ratios of crucial protein factors. This complexity is a consequence of the wide range of CYP3A ligands and of nuclear receptors mediating the induction of CYP3A genes [9][13].

3. Involvement of CYP3A Enzymes in Biological Processes

CYP3A enzymes have very broad substrate specificity and metabolize a wide range of compounds in terms of chemical and biological properties. They catalyze reactions of hydroxylation, N-demethylation, O-dealkylation, S-oxidation, deamination, and epoxidation [35] of endogenous and exogenous compounds. CYP3A perform physiological functions by taking part in such endogenous processes as steroid catabolism, bile acid metabolism, and lipid and vitamin D metabolism. CYP3A enzymes metabolize a wide variety of therapeutics and may play an important role in alterations of biological activities of drugs or in enhanced clearance of drugs as well as in drug interactions. For instance, CYP3A enzymes’ substrates are such endogenous compounds as hormones, cholesterol, bile acids, arachidonic acid, and vitamin D as well as the vast majority of drugs and of xenobiotics that are not pharmaceuticals [11][12][13].

4. CYP3A Involvement in Pathological Processes

Cholestasis is a pathological condition where normal flow of bile is low or disturbed, and bile acids accumulate in the liver. Stimulation of CYP3A4 activity in cholestasis may be an effective therapeutic approach to such diseases [19].

Arachidonic acid metabolites known as eicosanoids (EETs), whose emergence depends on CYP3A-mediated metabolism, are implicated in the pathophysiology of various diseases. For example, the CYP3A4 epoxygenase, responsible for the production of EETs, is overexpressed in breast cancer and is linked with the initiation and progression of breast cancer [36]. In human hepatoma cell line Hep3B, overexpression of CYP3A4 also promotes cell growth and cell cycle transition from the G1 to S phase [37].

The role of CYP3A enzymes in the metabolism of sex steroid hormones implies an association with the development of hormone-dependent diseases. It has long been known that CYP3A enzymes are expressed in normal and tumorous tissues of the breast [38][39][40] and of the prostate [41][42], in cells of the endometrium and cervix [43][44], and in ovarian tumors [45].

Vitamin D has multiple effects on the biological processes that regulate the metabolism of calcium and phosphorus and also affects proliferation, differentiation, and apoptosis of cells as well as immune regulation [46][47][48][49][50][51][52][53]. CYP3A4, by taking part in the inactivation of an active vitamin D metabolite [1.25(ОН)2D3], may have a significant impact on circulating vitamin D levels [54][55].

It is now clear that the expression and activity of CYP3A enzymes are affected by such pathological conditions as infection, inflammation, and cancer [10][56][57].

5. Concluding Remarks

This research is aimed at highlighting the main roles of CYP3A enzymes along with their unique characteristics in the metabolism of biologically active endogenous compounds and numerous xenobiotics that are important in clinical pharmacology as well as the involvement of these enzymes in a wide range of physiological and pathological phenomena. The scientific literature cited in this research attests to remarkable efforts and advances in the understanding how the CYP3A family of phase I biotransformation enzymes is integrated into the vast and complex network of physiological processes detoxifying endo- and xenobiotics. The function of CYP3A enzymes is complex because the effects of activation their genes are determined by a wide range of endogenous and exogenous ligands and by a unique regulatory system that involves CYP3A enzymes in many physiological and pathological processes in cells and tissues of the body (Figure 2).

Figure 2. Effects of CYP3A enzymes on the metabolism of endo- and xenobiotics have an influence on a wide range of physiological and pathophysiological processes in the body.

The totality of evidence indicates that the activation of CYP3A genes can be either beneficial or detrimental during diseases of various organs and tissues. The ultimate effects depend both on the context of a disease and on the nature of ligands of the nuclear receptors that control CYP3A genes’ transcription.

Currently, the molecular mechanisms by which CYP3A enzymes take part in pathogenesis are well understood only for a few diseases; in particular, a role of CYP3A5 in carcinogenesis has been demonstrated. There are more reports of (i) diseases associated with the participation of CYP3A enzymes in the metabolism of endogenous compounds and (ii) pathological conditions affecting the expression and activity of CYP3A enzymes. The consequence of an alteration of these enzymes’ activities is a change in the pharmacokinetics of the drugs used for treatment. Much basic research has been conducted on the role of CYP3A enzymes in pathological processes, but clinical studies that are aimed at influencing the mechanisms of signaling pathways regulating CYP3A genes in various diseases are still insufficient, and further investigation is needed.

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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Lyubov S. Klyushova
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Maria L. Perepechaeva
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Alevtina Y. Grishanova
View Times: 403
Revisions: 5 times (View History)
Update Date: 14 Nov 2022
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