Why We Need to Take a Closer Look at Genetic Contributions to CYP3A Activity

Zhai, Qinglian; Lee, Maaike van der; Gelder, Teun van; Swen, Jesse J.

doi:10.3389/fphar.2022.912618

Cited by 15 publications

(12 citation statements)

References 116 publications

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“…CYP3A plays a critical role in the metabolism of drugs and other exogenous and endogenous substances, and its function is modified by genetic factors (Zhai et al, 2022). CYP3A4*1G affects drug metabolisms by altering CYP3A4 expression and enzyme activity in vivo and in human liver tissues (Miura et al, 2011;He et al, 2014;Yuan et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

CYP3A4andCYP3A5Expression is Regulated by CYP3A4*1Gin CRISPR/Cas9-Edited HepG2 Cells

et al. 2023

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Functional CYP3A4*1G (G>A, rs2242480) in cytochrome P450 3A4 (CYP3A4) regulates the drug-metabolizing enzyme CYP3A4 expression. The objective of this study was to investigate whether CYP3A4*1G regulates both basal and rifampicin (RIF)-induced expression and enzyme activity of CYP3A4 and CYP3A5 in gene-edited human HepG2 cells. CYP3A4*1G GG and AA genotype HepG2 cells were established using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) single nucleotide polymorphism (SNP) technology and homology-directed repair (HDR) in the CYP3A4*1G GA HepG2 cell line. In CYP3A4*1G GG, GA, and AA HepG2 cells, CYP3A4*1G regulated expression of CYP3A4 and CYP3A5 mRNA and protein in an allele-dependent manner. Of note, significantly decreased expression level of CYP3A4 and CYP3A5 was observed in CYP3A4*1G AA HepG2 cells. Moreover, the results after RIF treatment showed that CYP3A4*1G decreased the induction level of CYP3A4 and CYP3A5 mRNA expression in CYP3A4*1G AA HepG2 cells. At the same time, CYP3A4*1G decreased CYP3A4 enzyme activity and tacrolimus metabolism especially in CYP3A4*1G GA HepG2 cells. In summary, we successfully constructed CYP3A4*1G GG and AA homozygous HepG2 cell models and found that CYP3A4*1G regulates both basal and RIF-induced expression and enzyme activity of CYP3A4 and CYP3A5 in CRISPR/Cas9 CYP3A4*1G HepG2 cells.

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Section: Discussionmentioning

confidence: 99%

CYP3A4andCYP3A5Expression is Regulated by CYP3A4*1Gin CRISPR/Cas9-Edited HepG2 Cells

et al. 2023

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“…8,9 It has been suggested that transcriptional regulators, such as HNF3γ and PXR, contribute to the observed variability in CYP3A4 activity. 2,10,11 More recently, associations between variants in the testis-specific Y-encoded-like proteins (TSPYLs) family and CYP3A activity have been reported. This family consists of TSPYL1 to TSPYL6, all of which are involved in many bio-functions, including chromatin remodeling 12 and transcriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

“…However, although it is estimated that 60%–80% of the variability of the enzyme activity is heritable, single nucleotide variants (SNVs) in the CYP3A4 gene only explain ~10% of the observed interindividual variability in CYP3A4 activity 8,9 . It has been suggested that transcriptional regulators, such as HNF3γ and PXR , contribute to the observed variability in CYP3A4 activity 2,10,11 …”

Section: Introductionmentioning

confidence: 99%

The effect of genetic variants in the transcription factor TSPYL family on the CYP3A4 mediated cyclosporine metabolism in kidney transplant patients

Zhai,

Moes,

van Gelder

et al. 2024

Clinical Translational Sci

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CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%–80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis‐specific Y‐encoded‐like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 in vitro. Here, we investigated the effect of genetic variants in TSPYL on CYP3A4 activity using data from a clinical study and a human liver bank. Five SNVs (rs3828743, rs10223646, rs6909133, rs1204807, and rs1204811) in TSPYL were selected because of a reported effect on CYP3A4 expression in vitro or suggested clinical effect. For the clinical study, whole blood concentrations, clinical data, and DNA were available from 295 kidney transplant recipients participating in the prospective MECANO study. A multivariate pharmacokinetic model adjusted for body weight, steroid treatment, and CYP3A4 genotype was used to assess the effect of the genetic variants on cyclosporine clearance. In multivariate analysis, homozygous carriers of rs3828743 had a 18% lower cyclosporin clearance compared to the wild‐type and heterozygous patients (28.72 vs. 35.03 L/h, p = 0.018) indicating a lower CYP3A4 activity and an opposite direction of effect compared to the previously reported increased CYP3A4 expression. To validate, we tested associations between rs3828743 and CYP3A4 mRNA and protein expression as well as enzyme activity with data from a liver bank (n = 150). No association with any of these end points was observed. In conclusion, the totality of evidence is not in support of a significant role for TSPYL SNV rs3828743 in explaining variability in CYP3A4 activity.

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“…Importantly, PXR and CAR are primarily expressed in the liver and gastrointestinal tract (Nishimura et al, 2004;Petrick and Klaassen, 2007) and are key transcription factors that govern the expression of genes encoding drug metabolizing enzymes including cytochrome P450s (CYPs) (Forman et al, 1998;Lehmann et al, 1998;Goodwin et al, 1999;Sueyoshi et al, 1999), UDP-glycosyltransferases (Sugatani et al, 2001;Sugatani et al, 2004), glutathione-S-transferases (Knight et al, 2008), sulfotransferases (Yetti et al, 2018), and drug transporters such as multidrug resistance protein 1 (MDR1) (Geick et al, 2001;Synold et al, 2001;Burk et al, 2005). A regulated gene set of particular note is the CYP3A family due to its known activity on the majority of clinically applied drugs (Zhai et al, 2022). PXR and CAR binding to chemicals results in subsequent nuclear translocation, binding to target gene promoters, and enhanced transcription.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond

2022

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Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are ligand-activated transcription factors that regulate the expression of drug metabolizing enzymes and drug transporters. Since their discoveries, they have been studied as important factors for regulating processes related to drug efficacy, drug toxicity, and drug-drug-interactions. However, their vast ligand-binding profiles extend into additional spaces, such as endogenously produced chemicals, microbiome metabolites, dietary compounds, and environmental pollutants. Therefore, PXR and CAR can respond to an enormous abundance of stimuli, resulting in significant shifts in metabolic programs and physiological homeostasis. Naturally, PXR and CAR have been implicated in various diseases related to homeostatic perturbations, such as inflammatory bowel disorders, diabetes, and certain cancers. Recent findings have injected the field with new signaling mechanisms and tools to dissect the complex PXR and CAR biology and have strengthened the potential for future PXR and CAR modulators in the clinic. Here, we describe the historical and ongoing importance of PXR and CAR in drug metabolism pathways and how this history has evolved into new mechanisms that regulate and are regulated by these xenobiotic receptors, with a specific focus on small molecule ligands. To effectively convey the impact of newly emerging research, we have arranged five diverse and representative key recent advances, four specific challenges, and four perspectives on future directions. SIGNFICANCE STATEMENTPXR and CAR are key transcription factors that regulate homeostatic detoxification of the liver and intestines. Diverse chemicals bind to these nuclear receptors, triggering their transcriptional tuning of the cellular metabolic response. This minireview revisits the importance of PXR and CAR in pharmaceutical drug responses and highlights recent results with implications beyond drug metabolism.

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Why We Need to Take a Closer Look at Genetic Contributions to CYP3A Activity

Cited by 15 publications

References 116 publications

CYP3A4andCYP3A5Expression is Regulated by CYP3A4*1Gin CRISPR/Cas9-Edited HepG2 Cells

CYP3A4andCYP3A5Expression is Regulated by CYP3A4*1Gin CRISPR/Cas9-Edited HepG2 Cells

The effect of genetic variants in the transcription factor TSPYL family on the CYP3A4 mediated cyclosporine metabolism in kidney transplant patients

Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond

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