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Schematic diagram of the CYP1A gene cluster on human chromosome 15. The DNA segment between the CYP1A1 and CYP1A2 genes was divided into three parts, named fragments 1, 2, and 3, respectively. These fragments were amplified by PCR as described under Materials and Methods. Closed boxes with numbers show the exons of the CYP1A1 and CYP1A2 gene. Positions of XRE sequence (5-TNGCGTG-3) are also indicated.
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The human CYP1A1 and CYP1A2 genes on chromosome 15 are orientated head-to-head and are separated by a 23-kilobase (kb) intergenic spacer region. Thus, the possibility exists for sharing common regulatory elements contained in the spacer region responsible for transcriptional activation and regulation of the CYP1A1 and CYP1A2 genes. In the present s...
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Context 1
... of a DNA Segment between CYP1A1 and CYP1A2 Genes. As shown in Fig. 1, approximately 27 kb of DNA segment (from 2420 of the CYP1A1 gene to 835 of the CYP1A2 gene) were divided into three parts, and each fragment was amplified by PCR with TaKaRa LA Taq (Takara Bio). A bacterial artificial chromo- some genomic clone containing the human CYP1A1 and CYP1A2 genes ( Corchero et al., 2001) was used as the ...
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... shown in Fig. 3, p1A1-204, which has no XRE, did not show an increase in reporter activities after treatment with BNF and 3-MC. Introduction of a single XRE (p1A1-887) showed approximately 12-fold increase of the reporter activ- ity in the presence of BNF. 3-MC treatment also resulted in an approximately 19-fold increase in reporter activity. Con- structs ...
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... bidi- rectionally. However, the potency in transcriptional activa- tion was different between the CYP1A1 and CYP1A2 genes. The transcriptional activation was much higher in the CYP1A1 gene than in the CYP1A2 gene. This result is partly consistent with the extent of induction of CYP1A1 and CYP1A2 mRNAs in HepG2 cells in response to BNF or 3-MC (Fig. ...
Citations
... Although developmental system drift is probably universal in long evolutionary periods (Palmer, 2004), it has been rarely possible to analyze whether there is selective advantage of such drifts. Co-expressed gene pairs sharing intergenic enhancers have been reported in various cases (Ueda et al., 2006;Sumiyama and Tanave, 2020;Zinani et al., 2021;Zinani et al., 2022), and often fall into the same functional categories (Zinani et al., 2022). In zebrafish, the paired her1 and her7 can provide robustness for segmentation patterning (Zinani et al., 2021). ...
A central goal of evolutionary developmental biology is to decipher the evolutionary pattern of gene regulatory networks (GRNs) that control embryonic development, and the mechanism underlying GRNs evolution. The Nodal signaling that governs the body axes of deuterostomes exhibits a conserved GRN orchestrated principally by Nodal, Gdf1/3, and Lefty. Here we show that this GRN has been rewired in cephalochordate amphioxus. We found that while the amphioxus Gdf1/3 ortholog exhibited nearly no embryonic expression, its duplicate Gdf1/3-like , linked to Lefty , was zygotically expressed in a similar pattern as Lefty . Consistent with this, while Gdf1/3-like mutants showed defects in axial development, Gdf1/3 mutants did not. Further transgenic analyses showed that the intergenic region between Gdf1/3-like and Lefty could drive reporter gene expression as that of the two genes. These results indicated that Gdf1/3-like has taken over the axial development role of Gdf1/3 in amphioxus, possibly through hijacking Lefty enhancers. We finally demonstrated that, to compensate for the loss of maternal Gdf1/3 expression, Nodal has become an indispensable maternal factor in amphioxus and its maternal mutants caused axial defects as Gdf1/3-like mutants. We therefore demonstrated a case that the evolution of GRNs could be triggered by enhancer hijacking events. This pivotal event has allowed the emergence of a new GRN in extant amphioxus, presumably through a stepwise process. In addition, the co-expression of Gdf1/3-like and Lefty achieved by a shared regulatory region may have provided robustness during body axis formation, which provides a selection-based hypothesis for the phenomena called developmental system drift.
... The base width of the AHR peaks in the promoters of CYP1A1 and CYP1B1, in contrast, is between 1000 to 3000bp, which reflects the nature of multiple AHR binding elements (AHREs) in these peak regions. Indeed, it had been shown that both mouse and human CYP1A1 and CYP1B1 genes contain 8 to 11 AHREs in the regions corresponding to the AHR peaks in ChIP-seq in this report [32][33][34]. Such an unusual enrichment of AHREs may render the resistance to As 3+ -induced reduction of AHR binding to CYP1A1 and CYP1B1 genes. ...
... One of the possible answers to this question is the number, location and surrounding sequences of the consensus AHR binding elements (AHRE), also called xenobiotic response elements (XRE) or dioxin response elements (DRE). It has been known that both CYP1A1 and CYP1B1 genes have multiple, 8 to 11, AHREs in the promoter or upstream of the genes [32][33][34]. It is possible, thus, that these multiple AHREs may enforce the transcriptional activation of the AHR. ...
As the most classic and extensively studied transcription factor in response to environmental toxic chemicals, the human aryl hydrocarbon receptor (AHR) has been implicated in mediating some oncogenic responses also. Limited information is available, however, on whether arsenic, a widely presented environmental carcinogen, can regulate AHR to exert its carcinogenic activity. Through chromatin immunoprecipitation and sequencing (ChIP-seq), CRISPR-Cas9 gene editing, RNA-seq, and immunohistochemistry (IHC), in this report we provided evidence showing that arsenic enforces TGFβ and other oncogenic signaling pathways in bronchial epithelial cells through disrupting the tumor suppressor-like activity of AHR. AHR is normally enriched on a number of oncogenic genes in addition to the known phase I/II enzymes, such as genes in TGFβ and Nrf2 signaling pathways and several known oncogenes. Arsenic treatment substantially reduced the binding of AHR on these genes followed by an increased expression of these genes. CRISPR-Cas9-based knockout of AHR followed by RNA-seq further demonstrated increased expression of the TGFβ signaling and some oncogenic signaling pathway genes in the AHR knockout cells. IHC studies on human tissue samples revealed that normal human lung tissues expressed high level of AHR. In contrast, the AHR expression was diminished in the lung cancer tissues. Accordingly, the data from this study suggest that AHR has tumor suppressor-like activity for human lung cancer, and one of the carcinogenic mechanisms of arsenic is likely mediated by the inhibition of arsenic on the tumor suppressor-like activity of AHR.
... With regard to CYP1A1 rs4646903, rs1048943 rs1799814 variants, no association was observed with asthma in allergic CRS subjects. Similarly, studies carried out on Caucasians, Japanese and Serbians also failed to confirm its role in COPD [35][36][37][38]. However, earlier studies on Japanese and Indian populations have shown CYP1A1 rs1048943 variant to be associated with COPD [39,40] indicating discrepancy in the role of CYPIA1 polymorphism in respiratory disorders. ...
Abstract Background Inter-individual differences in regulation and activity of xenobiotic metabolizing enzymes (XMEs) CYP1A and GST might cause distinct susceptibility to chronic rhinosinusitis (CRS) phenotypes that need to be explored. Therefore, the present study aimed to evaluate the role and risk of CYP1A and GST gene variants in allergic CRS subjects with and without asthma. A total of 224 allergic CRS cases with asthma, 252 allergic CRS cases without asthma, and 350 healthy control subjects were subjected to genetic analysis. Gene variants of cytochrome P450 (CYP1A1 T3801 rs4646903, A2455G rs1048943, C2453A rs1799814 and CYP1A2 G3858A rs2069514, T739G rs2069526, C163A rs762551) and glutathione S-transferase P (GSTP1 A313G rs1605 & C341T rs1799811) were investigated by polymerase chain reaction-restriction fragment length polymorphism and GSTM1null, and GSTT1null by multiplex PCR methods. Results TG genotype of CYP1A2 rs2069526 (OR 1.73, 95% CI 1.20–2.50, p
... Interestingly, the previous studies reported that HFD activated the aryl hydrocarbon receptor (AHR), which regulates lipid metabolism, vascular homeostasis, and metabolic dysfunction [33,34]. Also, the increases in CYP1A1 and CYP1A2 expressions responded to the AHR agonists and AHR-dependent pathway as demonstrated in mice, rat, and human hepatocytes [17,35,36], although there is the dose-response divergence between the expressions of these two enzymes [37,38]. Consequently, the increases in CYP1A2 activity and mRNA expression of the HFD-fed rats in this study might be attributed to the activation of AHR, which was afected by HFD ingestion. ...
Crocodile oil is a highly effective treatment for ailments ranging from skin conditions to cancer. However, the effects of the oil on liver detoxification pathways are not well studied. This study aimed to investigate the effects of crocodile oil on the detoxification enzyme activities and the mRNA expressions of cytochrome P450 1A2 (CYP1A2), cytochrome P450 2E1 (CYP2E1), and glutathione S-transferase (GST) in rats. The rats were divided into four groups (n = 7/group): rats received a standard diet (C), a high-fat diet or HFD (H), and HFD with 1 ml (HCO1) and 3 ml (HCO3) of the oil per kg body weight. Interestingly, the oil yields from this study presented alpha-linolenic acid (0.96%) at similar levels compared with fish oil. The results revealed that HFD significantly increased the activity and relative gene expression of CYP1A2 in the H group ( P < 0.05 ), whereas 3% crocodile oil normalized the enzyme activities compared to the C group. This suggested inhibiting the HFD-induced expression of CYP1A2 mediated by the omega-3 fatty acids found in the oil. Also, crocodile oil supplementation did not reduce the activities of GST. However, the relative gene expression of GSTA1 was significantly decreased ( P < 0.05 ) in the HCO1 and HCO3 groups compared to the H group, which might be attributed to the lower lipid peroxidation that occurred in the liver tissues. Therefore, it could be suggested that using crocodile oil could help in liver detoxification through the CYP1A2 even when offered with a HFD.
... However, genome sizes are significantly larger in higher organisms and as such the number of DPGs in eukaryotes are underestimated by the current standard. For example, human CYP1A1 and CYP1A2 genes are separated by a 23 kb intergenic region but are still coregulated through common regulatory elements [18]. Similarly, zebrafish her1 and her7 are separated by a 12 kb intergenic spacer region but are mostly coexpressed in the paraxial mesoderm [19]. ...
Coordinated spatiotemporal expression of large sets of genes is required for the development and homeostasis of organisms. To achieve this goal, organisms use myriad strategies where they form operons, utilize bidirectional promoters, cluster genes, share enhancers among genes by DNA looping, and form topologically associated domains and transcriptional condensates. Coexpression achieved by these different strategies is hypothesized to have functional importance in minimizing gene expression variability, establishing dosage balance to ensure stoichiometry of protein complexes, and minimizing accumulation of toxic intermediate metabolites. By combining gene-editing tools with computational modeling, recent studies tested the advantages of adjacent genes located in pairs and clusters. We propose that with the advancement of gene editing, single-cell sequencing, and imaging tools, one could readily test the functional importance of different coexpression strategies in a variety of biological processes.
... AhR is a gene battery that regulates a group of phase I as well as phase II enzymes (Anwar-Mohamed et al., 2009). The expression of CYP1A1, CYP1A2, CYP1B1, and CYP2S1 genes, which represent phase I group, is regulated by AhR response elements found in their promoters, therefore they are highly inducible by AhR ligands (Jorge-Nebert et al., 2010;Kerzee and Ramos, 2001;Saarikoski et al., 2005;Ueda et al., 2006). In humans, CYP1A1, CYP1A2, and CYP1B1 are constitutively expressed in the liver; however, only CYP1A2 is detected at much higher levels. ...
Arsenic is well-recognized as one of the most hazardous elements which is characterized by its omnipresence throughout the environment in various chemical forms. From the simple inorganic arsenite (iAsIII) and arsenate (iAsV) molecules, a multitude of more complex organic species are biologically produced through a process of metabolic transformation with biomethylation being the core of this process. Because of their differential toxicity, speciation of arsenic-based compounds is necessary for assessing health risks posed by exposure to individual species or co-exposure to several species. In this regard, exposure assessment is another pivotal factor that includes identification of the potential sources as well as routes of exposure. Identification of arsenic impact on different physiological organ systems, through understanding its behavior in the human body that leads to homeostatic derangements, is the key for developing strategies to mitigate its toxicity. Metabolic machinery is one of the sophisticated body systems targeted by arsenic. The prominent role of cytochrome P450 enzymes (CYPs) in the metabolism of both endobiotics and xenobiotics necessitates paying a great deal of attention to the possible effects of arsenic compounds on this superfamily of enzymes. Here we highlight the toxicologically relevant arsenic species with a detailed description of the different environmental sources as well as the possible routes of human exposure to these species. We also summarize the reported findings of experimental investigations evaluating the influence of various arsenicals on different members of CYP superfamily using human-based models.
... Typically, CYP1A1 and 1A2 are highly inducible by numerous xenobiotics that act as AhR ligands. Genes of these two CYP1A members are arranged in a head-to-head orientation, sharing a common bi-directional promoter with at least 13 AhR response elements [154,155]. Additionally, transactivation of both CYP1A promoters by CAR is also possible through a common cis-regulatory estrogen receptor element (ER8) in the 5 -flanking region [149]. Transcriptional regulation of CYP2A6 gene involves PXR and CAR activators via direct repeat 4 (DR4) elements [150]. ...
Human Cytochrome P450 (CYP) enzymes constitute a superfamily of membrane-bound hemoproteins that are responsible for the metabolism of a wide variety of clinically, physiologically, and toxicologically important compounds. These heme-thiolate monooxygenases play a pivotal role in the detoxification of xenobiotics, participating in the metabolism of many structurally diverge compounds. This short-review is intended to provide a summary on the major roles of CYPs in Phase I xenobiotic metabolism. The manuscript is focused on eight main topics that include the most relevant aspects of past and current CYP research. Initially, (I) a general overview of the main aspects of absorption, distribution, metabolism, and excretion (ADME) of xenobiotics are presented. This is followed by (II) a background overview on major achievements in the past of the CYP research field. (III) Classification and nomenclature of CYPs is briefly reviewed, followed by (IV) a summary description on CYP’s location and function in mammals. Subsequently, (V) the physiological relevance of CYP as the cornerstone of Phase I xenobiotic metabolism is highlighted, followed by (VI) reviewing both genetic determinants and (VI) nongenetic factors in CYP function and activity. The last topic of the review (VIII) is focused on the current challenges of the CYP research field.
... Activation of AHR action is through the AHR repressor and the induction of the cytochrome P450 enzymes CYP1A1, CYP1A2 and CYP1B1 (Larigot et al. 2018), which have high activity for the metabolism of estrogen (Lee et al. 2003;Tsuchiya et al. 2004). The CYP1A1 and CYP1A2 genes are bidirectionally positioned in the genome and are served by a common promoter region (Ueda et al. 2006) that is activated by AHR binding (Monostory et al. 2009). Polymorphisms in AHR have been shown to influence the expression of genes downstream in the pathways of AHR (CYP1A genes) and its own expression (Helmig et al. 2011). ...
Puberty in female pigs is defined as age at first estrus and gilts that have an earlier age at puberty are more likely to have greater lifetime productivity. Because age at puberty is predictive for sow longevity and lifetime productivity, but not routinely measured in commercial herds, it would be beneficial to use genomic or marker‐assisted selection to improve these traits. A GWAS at the US Meat Animal Research Center (USMARC) identified several loci associated with age at puberty in pigs. Candidate genes in these regions were scanned for potential functional variants using sequence information from the USMARC swine population founder animals and public databases. In total, 135 variants (SNP and insertion/deletions) in 39 genes were genotyped in 1284 phenotyped animals from a validation population sired by Landrace and Yorkshire industry semen using the Agena MassArray system. Twelve variants in eight genes were associated with age at puberty (P < 0.005) with estimated additive SNP effects ranging from 1.6 to 5.3 days. Nine of these variants were non‐synonymous coding changes in AHR, CYP1A2, OR2M4, SDCCAG8, TBC1D1 and ZNF608, two variants were deletions of one and four codons in aryl hydrocarbon receptor, AHR, and the most significant SNP was near an acceptor splice site in the acetyl‐CoA carboxylase alpha, ACACA. Several of the loci identified have a physiological and a genetic role in sexual maturation in humans and other animals and are involved in AHR‐mediated pathways. Further functional validation of these variants could identify causative mutations that influence age at puberty in gilts and possibly sow lifetime productivity.
... In humans, transcriptional activation of the CYP1A1 and CYP1A2 genes is controlled simultaneously by a dual promoter construct existing between these two genes and acting bidirectionally. The promoter contains arylhydrocarbon receptor (AhR) response elements (Ueda et al. 2006;Jorge-Nebert et al. 2010). Expression of nuclear AhR may be higher in a particular brain area than in the liver. ...
The regulation of brain cytochrome P450 enzymes (CYPs) is different compared with respective hepatic enzymes. This may result from anatomical bases and physiological functions of the two organs. The brain is composed of a variety of functional structures built of different interconnected cell types endowed with specific receptors that receive various neuronal signals from other brain regions. Those signals activate transcription factors or alter functioning of enzyme proteins. Moreover, the blood-brain barrier (BBB) does not allow free penetration of all substances from the periphery into the brain. Differences in neurotransmitter signaling, availability to endogenous and exogenous active substances, and levels of transcription factors between neuronal and hepatic cells lead to differentiated expression and susceptibility to the regulation of CYP genes in the brain and liver. Herein, we briefly describe the CYP enzymes of CYP1-3 families, their distribution in the brain, and discuss brain-specific regulation of CYP genes. In parallel, a comparison to liver CYP regulation is presented. CYP enzymes play an essential role in maintaining the levels of bioactive molecules within normal ranges. These enzymes modulate the metabolism of endogenous neurochemicals, such as neurosteroids, dopamine, serotonin, melatonin, anandamide, and exogenous substances, including psychotropics, drugs of abuse, neurotoxins, and carcinogens. The role of these enzymes is not restricted to xenobiotic-induced neurotoxicity, but they are also involved in brain physiology. Therefore, it is crucial to recognize the function and regulation of CYP enzymes in the brain to build a foundation for future medicine and neuroprotection and for personalized treatment of brain diseases.
... The promoter region of CYP1A1 and CYP1A2 genes contains several Aryl hydrocarbon receptor (AhR) response elements [42,43], which, after binding of respective compounds, initiate coordinated transcription of both genes. Consequently, both genes are highly inducible by AhR ligands such as polycyclic aromatic hydrocarbons (PAHs), dioxins and numerous xenobiotics [44]. ...
Cytochrome P450 (CYP) 1A enzymes are considerably expressed in the human intestine and liver and involved in the biotransformation of about 10% of marketed drugs. Despite this doubtless clinical relevance, CYP1A1 and CYP1A2 are still somewhat underestimated in terms of unwanted side effects and drug-drug interactions of their respective substrates. In contrast to this, many frequently prescribed drugs that are subjected to extensive CYP1A-mediated metabolism show a narrow therapeutic index and serious adverse drug reactions. Consequently, those drugs are vulnerable to any kind of inhibition or induction in the expression and function of CYP1A. However, available in vitro data are not necessarily predictive for the occurrence of clinically relevant drug-drug interactions. Thus, this review aims to provide an up-to-date summary on the expression, regulation, function, and drug-drug interactions of CYP1A enzymes in humans.
