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]^[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]^[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 [3,7]^[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 [5,6,8-10]^{[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]^[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 [11,12,14]^[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]^[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]^[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].

1.1. Members of the CYP3A Subfamily: Localization of Genes in the Genome and of Enzymes in Tissues of the Body2. Mechanisms of CYP3A Regulation

ToCYP3A4 date, four functional enzymes belonging to the CYP3A subfamily have been identified in humans: CYP3A4, CYP3A5, CYP3A7, and CYP3A43 [5,6,8,9]. Each gene contains 13 exons with conserved exon–intron boundaries [10,19]. CYP3A isoenzymes are expressed mainly in the liver and small intestexpression is modulated by various mechanisms involving nuclear receptors, hormones, xenobiotics, and signaling molecules. CYP3A4 ine as well as in the kidneys, adrenal glands, lungs, brain, prostate, testes, placenta, pancrearegulated by a large number of xenobiotics, including many drugs, endogenous compounds, and skeletal muscles [5,6,8,9,11,14,20-23].

Inmany hormones, tsuche CYP3A subfamily, CYP3A4 is the major member participating in drug metabolism and is the predominant form as triiodothyronine, dexamethasone, and growth hormone ^[19].

Xenof CYP3A bin the liver (10–50%) and small intestine (40%) of adult humans. CYP3A5 is the most abundanotic- and endobiotic-mediated CYP3A4 induction is indirect and best studied among minor isoforms of CYP3A [6,8]. CYP3A7 and CYP3A43 are underexpressed as compared to CYP3A4/5 [6,8]. Protein expression of CYP3A43 in human liver microsomes is ~15 times lower than that of CYP3A4 [24]. CYP3A7, a predominantly fetoplacental enzyme, is highly expressed in the 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 and intestines of the embryo and fetus aX 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 bin the endometrium andding to the three major plcis-acetinta, although it is detectable in the liveg modules: CLEM4, distal XREM, and prPXRE (Figure 1) ^[10].

Figure 1. Tr and small intestine of some adults [5,6,8,12,23,25]. Among the CYP3A scriptional regulation of CYP3A4. Pregenes, CYP3A43 was thne last to be identified. CYP3A43 expression is highest in the prostate (the organ with intensive metabolism of steroids)X receptor (PXR), constitutive androstane receptor (CAR), and vitamin D receptor (VDR) control basal and in the brain: [26].ducible expression of CYP3A43 is also found in the testes, liver through competitive binding to the same set of response elements (everted repeats 6, kER6; didneys, placentarect repeats DR3, and pancreas [5,6,8,9,14,20,21].

2. Mechanisms of CYP3A Regulation

2.1. Constitutive Regulation of CYP3A4 Transcription

CDR4). PXR, CAR, onstitutiver VDR regulation ofunbound by CYP3A4a trliganscription, both positive and negative, is mediated by hepatocyte nuclear factor 4α (HNF4α) and other hepatic transcription factors, including HNF1α and HNF3γ [27-31], CCAAT/enhancer-bindingd is located in the cytoplasm as a complex with heat shock protein 90 (HSP90) or cytoplasmic constitutive active/androstane receptor retention proteins alpha and beta (C/EBPα and C/EBPβ), and upstream transcription factor 1 (USF1) [10,32] via binding to three major (CCRP). When activated by a ligand, each of them forms cis-ac heting modules: constitutive liver enhancer module 4 (CLEM4) (positions −11.4 to −10.5 kbp), the distal xenobiotic-erodimer with retinoid X receptor α (RXRα), relocates to the nucleus, binds to a responsive enhancer module (XREM) (−7.2 to −7.8 kbp) and the proximal promoter (prP) [10].

Whee element, recruits coactivators, an bound to DNA, HNF4α attract activates CYP3A4 transcription. coactivators and other accessory proteins and positively regulatesEstrogen receptor (ER) and glucocorticoid receptor (GR) raise CYP3A4 expression by enhancing the expression of target genes. In the liver, HNF4α is located exclusively in the nucleus and CAR, RXRα, and PXR. Ligand-activated farnesoid X receptor (FXR) upregulates the constitutive expression of a large number of target genes, includsmall heterodimer partner (SHP), which prevents the recruitment of coactivators to chromatin and/or forms heterodimers with RXRα, thereby inhibiting CYP3A4 [33].

2.2. Regulation of CYP3A4 Transcription

CYP3A4 expression. is modulated by various mechanisms involving nuclear Histone deacetylase 1 (HDAC1) inhibition by carbamazepine downregulates CYP3A4. Liver X receptors, hormones, xenobiotics, and signaling molecules. (LXR) forms a heterodimer with RXRα that then binds to CYP3A4DR4 isn regulated by a large number of xenobiotics, including many drugs, endogenous compounds, and many hormones, such as triiodothyronine, dexamethasone, and growth hormone [34].

the target gene, thus repressing its expression. After the binding of a ligand to LXR or RXR, thenobiotic- 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 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; (PPARαPPARα) [10,11,14,35-50] as well as by binding to the three majo its protein product binds as a PPARα–RXRα heterodimer cis-actingo modules: CLEM4, distal XREM, and prPXRE [10].

Nucletifs DR1 and DR2 arnd receptors participating in the regulaenhances the transcription of CYP3A4 sharend PXR. proteLin partners, ligands, DNA-sensing elements, and targegand-activated PXR suppresses PPARα-dependent genes, thereby forming a complex regulatory network by which the cell adapts to changes in its chemical environment [9,14].

2.3. Negative Regulation of CYP3A Enzymes

Su expression by inhibiting peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) recruitment. Hyppressoxion of CYP3A gea and inflammationes is mediated by nduce the activationity of nuclear factor kappa B (NF-κB) [51]. In addition, tumor necrosis factor (TNF) attenuates PXR-mediatedand promote a release of the cytokines that increase the transcriptional activation induce of CCAAT enhancer-binding protein beta (C/EBPβ) and bythe rifampicin in vitrtranslation o [51,52]f C/EBPβ-LIP mRNA. C/EBProteins p53, NF-κB,β-LIP competes with C/EBPα and C/EBP-LIP are involvedβ-LAP for binding to response elements in the repressionpromoter of CYP3A4, gene activity [9]thus lowering its expression. NF-κB activation plays an important role in thees miR-155, which directly targets mRNAs of suppressors of cytokine signaling proteins (especially suppressionor of CYP3A gecytokine s by disrupting the binding of the PXR–RXRα complex to DNA [53]. Cytokine-mediated downignaling 1: SOCS1) thereby inhibiting obligatory negative feedback regulation of CYP3A4 during the inflammatory responses. viaAbbreviations. theC/EBPβ-LAP: Janus kinase (JAK)–signal transducer ana C/EBPβ isoform called liver-enriched activator of transcription (STAT) pathway is of great importance [10].

2.4. An Additional Level of Regulation of CYP3A Genes

2.4.1. Epigenetic Mechanisms of CYP3A Gene Regulation

Exprotein; C/EBPβ-LIP: a C/EBPβ isoform called liver-enriched inhibitory protession of CYP genes is influenced by epigeneticin; COUP-TFI: chicken ovalbumin upstream promoter transcription factors including histone modifications, DNA methylation, and regulation by noncoding RNAs [54].

2.4.2. Genetic Polymorphisms of CYP3A Genes and Their Influence on the Activity of CYP3A Enzymes

I; COUP-TFII: chicken ovalbumin upstream promoter transcription factor II; DR1, DR2, DR3, DR4, and ER6: AG(G/T)TCA-lthough members of the CYP3A subfamily share high identity of amino acid and DNA sequences, their tissue- and age-specific expression patterns and substrate specificity differ considerably [55]. Genetic polymorphisms are a major cause of inter-individual differenceike 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, inmost CYP3A expression and functiinducers act through transcriptional activation [^[9][11][13]. CYP3,56].

2.4.3. CYP3A Inducers

LA igsoforms ands of nuclear receptors modulating CYP3A expression are presented in Figure 4.

Figure 4. Liginvolved in their regulation are subject (as part of post-transcriptional regulation) to ubiquitination (CYP3A4 ands of nuclear receptors modulating CYP3A CYP3A5) and phosphorylation (CYP3A4 and PXR) ^[11], whexpression.

2.4.4. CYP3A Inhibitors

as post-translational regulation of CYP3A enzymes mconsists of thetabolize stabilization of CYP3A mRNAs and proteins ^[6][11].

Molecular variety of compoundsmechanisms of induction may differ among whichthe four major human CYP3A genes alnd amost the only common feature is lipophilicity and relatively large size; therefore, it is not surprising that manyng 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 these compounds act as inhibitors wide range of CYP3A ligands and of nuclear receptors mediating the induction of CYP3A genzymes [57]^[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 [23] ^[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 [11,12,14]^[11][12][13].

4. CYP3.1. Metabolism of Endogenous CompoundA Involvement in Pathological Processes

3.1.1. Biotransformation of Cholesterol and Bile Acids by CYP3A Enzymes

CYP3A enzymes are involved in cholesterol and bile acid metabolic pathways [58-60]. Cholesterol is metabolized to 4β-hydroxycholesterol [13] and to 25-hydroxycholesterol by CYP3A4 and CYP3A5 [13,61].

CYP3A enzymes particasis is a pathological condipate in bile acid biotransformation [58-60]. CYP3A enzymes are associated with a minor pathway for the biosynthesis of primary cholateion where normal flow of bile acids. 25-Hydroxylation of 5β-cholestan-3α,7α,12α-triol, which is an intermediate in the biosynthesis of cholic acid, is catalyzed by CYP3A4 and CYP3A5 [62].

3.1.2. Biotransformation of Hormones by CYP3A Enzymes

CYP3A is low or disturbed, and bile acids accumulate in thenzymes play an important part in hormonal homeostasis. With regard to steroid hormones, theliver. Stimulation of CYP3A subfamily plays an important role in the metabolism of androgens (testosterone, androstenedione, dehydroepiandrosterone, and dihydrotestosterone), progesterone, cortisol, and their metabolites [10,12,14].

3.1.3. Biotransformation of Vitamin D by the CYP3A Subfamily

In 4 activity in cholestasis may be an effective the liver and small intestine, CYP3A4 and CYP3A5 are involved in vitamin D metabolism [22]apeutic approach to such diseases ^[19].

3.1.4. Biotransformation of Arachidonic Acid by CYP3A Enzymes

Arachidonic acid is the prmecursor to various physiologically active molecules such as epoxytabolites known as eicosatrienoic acnoids (EETs), whichose are a class of functionally bioactive lipid emergence depends on CYP3A-mediators derived from the meed metabolism of long-chain polyunsaturated fatty acids under the action of multiple enzymes of three main families, including cyclooxygenases, lipoxygenases, and cytochromes P450 [63,64].

3.2. Biotransformation of Exogenous Compounds

The substrates of , are implicated in the pathophysiology of various diseases. For example, the CYP3A4 enzymes are a wide range of prescription drugs as well as xenobiotics such as carcinogens benzo[a]poxygenase, respyrene, 7,8-dihydrodiol, and atlatoxin B [65,66].

CYP3A enzymes can metansibolize many structurally and functionally distinct classes of drugs [34,67-77]. The involvement of CYP3A enzymes in the metabolism of most drugs underlies their main biomedical significance as enzymes that influence drug kinetics and as participants in drug interactions.

3.3. Endogenous and Exogenous Biomarkers of Activity of CYP3A Enzymes

Accure for the production of EETs, is overexpressed in breast cancer and is linked with the initiation atend predictions of the activity of CYP3A enzymes are needed to provide effective pharmacotherapyogression of breast cancer to^[36]. predict treatmeInt outcomes or potential adverse effects of various therapeutic agents and to assess the development and progression of diseases.

Research human hepatoma cell line is undHerway for identifying optimal endogenous biomarkers of the activity of CYP3A enzymes, e.g., derivatives of cholesterol, of bile acids, or of steroid hormones, which can be quantified by measuring the concentration of certain compounds in a urine or blood sample without the introduction of xenobiotics into the human body [78]. Appropriate combinations of such markersp3B, overexpression of CYP3A4 also promotes cell growth and cell cycle transition from the G1 to S phase s^[37].

Thould make it possible to predict the activity orole of CYP3A enzymes while taking into account contributions of different isoforms [11].

4. CYP3A Involvement in Pathological Processes

4.1. Diseases Related to the Participation of CYP3A Enzymes in Bile Acid Metabolism

Cholin the mestasis is a pathological condition where normal flow of bile is low or disturbed, and bile acids accumulate in the liver. The reason is either mechanical obstruction of bile ducts or defects in hepatic transporters [79]. The outcome is inflammation and damage to the bile ducts, followed by exposure of hepatocytes to high concentrations of bile acids, which can result in hepatocyte death [79,80]. For control over processes in the gastrointestinal tract in cholestatic conditions, the composition of bile acids and the size of their pool are important, and hydrophobic bile acids are especially cytotoxic [80,81].

Stimulatiobolism of sex steroid hormones implies an association with the development of hormone-depen of CYP3A4 activity in choldestasis may be an effective therapeutic approach to such nt diseases [34].

New Itherapeutic approaches are being developed for the treatment of cholestatic pathologies, including agonists of FXR, which mediates the induction of CYP3A4 expression by bile acids [82]. Furthermore, other derivatives of natural bile acids have been proposed: “bile mimetics,” such as nor-ursodeoxycholic acid and obeticholic acid, which is a potent FXR agonist [83].

4.2. Diseases Associated with the Participation of CYP3A Enzymes in Arachidonic Acid Metabolism

A has long been known that CYP3A enzymes are expressed in norachidonic acid metabolites known as eicosanoids (EETs), a sal and tubclass mof oxylipins, have a wide range of physiological effects in cardiovascular homeostasis and regulation of cell growth, inflammation, and immune responses. EETs function rous tissues of the breas regulators of c^[38][39][40] ardiac, vascular [84-87], and renal physiology [88-90]. In the cardiovascular systemof the prostate ^[41][42], EETsin scerve as vascular relaxation factors independent of nitric oxide and prostacyclin I2 [91].

Eicoslls of the endometrium anoids (EETs), whose em cergence depends on CYP3A-medviatedx metabolism^[43][44], are implicatend in the pathophysiology of various diseases.

4.3. Roles of CYP3A Enzymes in Diseases Associated with the CYP3A Involvement in the Metabolism of Sex Steroids

The role of CYP3A e ovarianzymes in the metabolism of sex steroid hormonetumors implies an association with the development of hormone-dependent diseases^[45].

4.4. Diseases Related to the Participation of CYP3A Enzymes in Vitamin D Metabolism

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 and hence calcium homeostasis, which in turn may influence bone and immune-system health [92,93] by downregulating the overexpression of inflammatory cytokines such as IL-1α, IL-1β, and TNF [94,95]^[54][55].

It is possible that the progression of cardiovascular diseases may be due to the inactivating effect of CYP3A4 on the active form of vitamin D because a low concentration of 1,25(OH)₂D₃ in bow clood serum is strongly associated with the initiation of cardiovascular diseases [96] and with the incidence of arterial hypertension [97].

4.5. Changes in the Expression and Activity of CYP3A Enzymes in Various Pathological Conditions

It is now clear tar that that the expression and activity of CYP enzymes are affected by such pathological conditions as infection, inflammation, and cancer [10,98,99].

4.5.1. Inflammation-Dependent Changes in the Expression and Activity of CYP3A Enzymes

The influence of inflammation on the expression of CYP3A enzymes is an important topic because an alteration of these enzymatic activities leads to a change in pharmacokinetics of prescription drugs. Inflammation is a common sign of many diseases and is implicated in the pathogenesis of such illnesses as infectious diseases, cancer, diabetes mellitus, rheumatoid arthritis, and inflammatory bowel disease as well as age-related processes such as normal aging and metabolic aberrations [100]. Sources of inflammation are infections, e.g., hepatitis, human immunodeficiency virus (HIV) infection, and COVID-19 [101]. Aside from infections, other possible sources of inflammation in the human body are diseases of organs (the kidneys, liver, lungs, and heart), diabetes mellitus, autoimmune diseases (ankylosing spondylitis, psoriasis, systemic lupus erythematosus, Crohn’s disease, and celiac disease), and cancer. Additionally, possible sources of inflammation are vaccination, a surgical procedure, a critical condition of a patient, and treatment with immunomodulatory agents, anti-TNF antibodies, or monoclonal antibodies [101].

Ire affected by such pathological conditions as in such disease states, the regulation of CYP enzymes is connected with inflammation status [100]. It is recognized that changes related to CYP enzymes are a common consequence of the immunostimulation following infection and inflammation [102,103]. The source of modulation of CYP enzymes’ activities is endogenous infection, inflammation markers: cytokines, adipokines, lipid metabolites of nitric oxide, proteases, and reactive oxygen species [104]. Inflammation is accompanied by suppression, and cancer of the CYP enzymes that metabolize xenobiotics, including medical drugs [105]^[10][56][57]. The most studied CYP subfamily in inflammation is CYP3A [101].

4.5.2. Aberrant Intratumoral Expression of CYP3A Enzymes

5. Concluding Remarks

The main clinical consequences of aberrant intratumoral expression of CYP3A4 may be mediated by administration of anticancer drugs that are CYP3A substrates during the treatment of Ewing’s sarcoma. Local expression of CYP3A enzymes in malignant tissue may contribute to the development of multidrug resistance or toxicity observed in this type of tumor.

Recent investigation into the aberrant expression of CYP3A5 in cancer, depending on the malignancy and ability to metastasize, uncovered a role of CYP3A5 in cancer progression, metastasis, and invasion.

5. Concluding Remarks

This revies review 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 review 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 52).

Figure 52. 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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