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The Aryl Hydrocarbon Receptor Regulates an Essential Transcriptional Element in the Immunoglobulin Heavy Chain GeneWourms, Michael J. January 2013 (has links)
No description available.
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Investigation of cytochrome p450 isoforms 1A1, 1B1 and 2W1 as targets for therapeutic intervention in head and neck cancer. Probing CYP1A1, 1B1 and 2W1 activity with duocarmycin bioprecursorsPresa, Daniela January 2018 (has links)
The full text will be available at the end of the embargo: 30th July 2026
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Isolation and Functional Characterization of a Dioxin-Inducible CYP1A Regulatory Region From Zebrafish (<em>Danio rerio</em>)ZeRuth, Gary T 11 April 2008 (has links)
Cytochrome P4501A1 (CYP1A1) is a phase I bio-transformation enzyme involved in the metabolism of xenobiotics via the oxygenation of polycyclic aromatic hydrocarbons (PAHs) including the carcinogen, benzo(a)pyrene. Induction of the CYP1A1 gene is regulated at the transcriptional level and is ligand dependent with the prototypical 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) being the most potent known inducer of CYP1A1 transcription. This process is mediated by the AHR/ARNT signaling pathway whereby ligand binds AHR in the cytoplasm allowing its translocation to the nucleus where it binds with its hertrodimerization partner, ARNT and subsequently binds DNA at cognate binding sites termed xenobiotic responsive elements (XREs) located in the 5' flanking region of the CYP1A1 and other genes.
The zebrafish (Danio rerio) has recently become an important model system for the study of TCDD-mediated developmental toxicity due to their relative ease of maintaining and breeding, external fertilization, abundant transparent embryos, and sensitivity to TCDD similar to mammalian models. It is therefore essential to vii characterize the molecular mechanisms of AHR mediated gene regulation in this organism.
The upstream flanking region of a putative CYP1A gene from zebrafish was identified by the screening of a PAC genomic library. Sequencing revealed a region which contains 8 putative core xenobiotic response elements (XREs) organized in two distinct clusters. The region between -580 to -187 contains XRE 1-3 while the region between -2608 to -2100 contains XRE 4-8. Only XRE 1, 3, 4, 7, and 8 exhibited TCDD-dependant association of AHR/ARNT complexes when evaluated by gel shift assays. The use of in vitro mutagenesis and Luciferase reporter assays further showed that only XRE's 4, 7, and 8 were capable of conveying TCDD-mediated gene induction. The role of nucleotides flanking the core XRE was investigated through the use of EMSA and reporter assays. Similar methods were employed on additional transcription factor binding sites identified by in silico analyses revealing two sites conforming to an HNF- 3α and CREB motif, respectively, which demonstrate importance to regulation of the gene.
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Microarray Applications For Determination Of The Effects Of Emodin On Breast Cancer Cell LinesQomi Ekenel, Emilia 01 March 2011 (has links) (PDF)
ABSTRACT
MICROARRAY APPLICATIONS FOR DETERMINATION OF THE EFFECTS OF EMODIN
ON BREAST CANCER CELL LINES
Ekenel Qomi, Emilia
M.S., Department of Biotechnology
Supervisor: Prof. Dr. Mesude Iscan
Co-Supervisor: Assoc. Prof. Dr. Nursen Ç / oruh
February 2012, 191 pages
Cancer is a genetic disease that is characterized by uncontrolled cells growth. Breast
cancer is a type of cancer originating from breast tissue. Some breast cancers are
sensitive to hormones such as estrogen which makes it possible to treat them by
blocking the effects of these hormones in the target tissues. These require less
aggressive treatment than hormone negative cancers. Breast cancers without
hormone receptors, are higher-risk, and are treated more aggressively.
The aim of our study is to investigate the effect of emodin on MCF-7 which is ER
(estrogen receptor) positive, and MDA-MB-231 (ER negative) cancerous cell lines.
Emodin which is a phytoestrogen component, extracted from rheum (genus) plant,
has been reported to suppress the growth of tumor in some clinical situation, and
it&rsquo / s found that emodin induced apoptosis through the decrease of Bcl-2/Bax ratio
and the increase of cytoplasm cytochrome c concentration in human breast cancer
Bcap-37 cells. Comparing the effect of emodin between ER positive and ER negative
cells at the molecular level was investigated by Microarray analysis of gene
expressions using Affymetrix Human Genome U133 plus 2.0 Array. The microarray
data analysis was performed by using BRB-Array Tools, v.4.2.0.
GST and its classes / Alpha, Mu, Pi, Theta, Sigma, Omega, Zeta and Kappa is our
interested genes because of its role in regulating susceptibility to cancer, by their
ability to metabolize reactive electrophilic intermediates to usually less reactive and
more water soluble glutathione conjugates. And also its have a role in detoxifying
the damage caused by oxidative stress which is a result of the radiotherapy.
v
The differentially expressed genes from emodin treated and untreated control
breast cancer cell lines were compared after normalization and filtering and
annotated, it was shown that the top 10 highly (significantly) varied genes belong to
the biological processes such as (namely) cell cycle, cell division, cell proliferation,
mitosis and meiosis, this insure the relation of emodin to the cell growth processes
in the cancerous cells. The analysis of the change on the cell growth confirmed the
anti-tumor effect of emodin.
About the effect of emodin treatment on MCF-7 and MDA-MB-231 cancerous cell
lines separately / Both cells its significant genes was belong to cell growth biological
processes, in MCF-7 cells in-addition other biological processes was shown, for
example / stimulus to estradoil response, and the metabolism of xenobiotic by
cytochrome p450, so CYP1A1 gene code for a protein which is used in emodin
metabolism. The varied gene number was nearly 4400 gene from the scatter plot
result in MCF-7 cells while in MDA-MB-231 cells it was nearly 3400 gene, these
result insured the effect of emodin as a phytoestrogenic component as MCF-7 cells
are ER positive cells, so emodin bind to the ER in MCF-7 cells and affected more
gene number than MDA-MB-231.
More number of GST enzyme classes changed in MCF-7 cells than MDA-MB-231,
and the effect of emodin as anti-cancer showed different change of GST genes
between MCF-7 and MDA-MB-231.
The results confirmed by network analysis done, to find the most related genes to
our top 10 regulated gene list, and these genes were analyzed / most of them where
in our gene list, and their regulation after emodin treatment analyzed and the result
was supported to emodin as anti-tumor and phytoestrogenic component.
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Functional domains of P450 1A1 and 1A2 molecular modeling-guided structure-function study /Tu, Youbin. January 1900 (has links)
Thesis (Ph. D.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains vii, 143 p. : ill. (some col.). Includes abstract. Includes bibliographical references.
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Regulation of P-glycoprotein and ABCP transportersKolwankar, Dhanashri R. January 1900 (has links)
Thesis (Ph. D.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains x, 123 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 113-123).
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Investigating the Effect of Rutaecarpine on the Benzo[a]pyrene-Induced DNA Damage in vitroLi, You 01 January 2019 (has links)
Benzo[a]pyrene (BaP), is one of the most potent mutagens and carcinogens known. It requires metabolic activation through cytochrome P450 (CYP)1A1 to yield the ultimate carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE can bind to DNA and form predominantly covalent (+) trans adducts at the N2 position of guanine causing DNA damage. Rutaecarpine (RTC) is an herbal medicine that has been used to treat several diseases such as headache, hypertension, gastrointestinal disorders, amenorrhea, and anti-inflammation. It has also been reported as a potent inducer of CYP enzymes, including CYP1A1, and CYP1A2. The mechanisms underlying up-regulation of CYP1A1 by RTC is dependent on aryl hydrocarbon receptors. Meanwhile, RTC can inhibit the activity of CYP1A1, CYP1A2 and CYP1B1.
To investigate the effect of RTC on the BaP-induced DNA damage, we analyzed the CYP1A1 enzyme activity and DNA damage level in two cell lines, namely mucoepidermoid pulmonary carcinoma cells (H292) and hepatocellular carcinoma cells (Hep3B). The cells either were treated with only 5 μM BaP or 1.25, 2.5, 5 and 10 μM RTC, respectively; or were co-administrated 5 μM BaP and one of the four concentrations of RTC for 24 hours. Ethoxyresorufin-O-deethylase (EROD) assay was used to detect CYP1A1 enzyme activity. The results showed that both BaP and RTC significantly (p<0.05) induced CYP1A1 enzyme activity when administered separately, with RTC induction exhibiting a concentration-dependent manner. Interestingly, co-administration of RTC with BaP, especially at high concentration (10 μM) of RTC, induced less CYP1A1 enzyme activity compared to either only RTC or BaP administration. MuseTM Multi-Color DNA Damage kit was used to evaluate the DNA damage level in cells. The data showed that the DNA damage induced by BaP alone was about 2-fold higher (p&;lt;0.05) than that by concurrent administration of RTC and BaP.
In conclusion, our data showed that although both RTC and BaP are inducers of CYP1A1 enzyme, their co-administration will reduce CYP1A1 enzyme activity compared with BaP administration alone. The DNA damage kit results supported that there is a potential protective effect of RTC against BaP-induced DNA damage in both H292 and Hep3B cells.
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Genetic Diversity and Expression Variation in Human Cytochrome P450 GenesJian, Zhengwen 23 April 2008 (has links)
No description available.
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Modification of the duocarmycin pharmacophore enables CYP1A1 targeting for biological activityPors, Klaus, Loadman, Paul, Shnyder, Steven, Sutherland, Mark, Sheldrake, Helen M., Guino, M., Kiakos, K., Hartley, J.A., Searcey, M., Patterson, Laurence H. January 2011 (has links)
No / The identification of an agent that is selectively activated by a cytochrome P450 (CYP) has the potential for tissue specific dose intensification as a means of significantly improving its therapeutic value. Towards this goal, we disclose evidence for the pathway of activation of a duocarmycin analogue, ICT2700, which targets CYP1A1 for biological activity.
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Veränderungen in der Genexpression fremdstoffmetabolisierender Enzyme und Bedeutung genetischer Polymorphismen unter besonderer Berücksichtigung von HIV-VirustatikaGashaw, Isabella 20 October 2003 (has links)
Die Therapie der HIV Infektion besteht aus Kombination mehrerer antiretroviraler Substanzen und birgt ein erhöhtes Risiko an Arzneimittelwechselwirkungen. Das bekannte Problem der Virusresistenz kann zudem durch Enzyminduktion begünstigt werden. Das Ziel der vorliegenden Arbeit lag in Untersuchungen zu Einflüssen der Virustatika auf die Expression von Cytochrom P450 Enzymen: 1A1, 1B1, 3A4 sowie der P-Glykoproteins (MDR1) an immortalisierten Zellsystemen. Die Protease Inhibitoren Indinavir, Nelfinavir, Ritonavir und Saquinavir induzierten die Regulation der mRNA Expression über den Aryl-Kohlenwasserstoff-Rezeptor (AhR) und den Pregnan-X-Rezeptor (PXR) dosisabhängig und signifikant. Die Nukleosidischen Reverse Transkriptase Inhibitoren Zalcitabin, Zidovudin und Lamivudin sowie der Nicht-Nukleosidische Inhibitor Nevirapin zeigten induktive Eigenschaften nur für die AhR Zielgene CYP1A1 und CYP1B1. Amprenavir und Efavirenz aktivierten die PXR-Regulation. Die möglichen Auswirkungen der Induktion der untersuchten Gene wurden ausführlich diskutiert. Die molekularen Grundlagen der interindividuell variierenden Aktivität von CYP3A wurden in einer Probandenstudie untersucht. Es wurden die mRNA Expression in den Leukozyten, die Aktivität des Enzyms und einige bekannte Polymorphismen unter Einwirkung von Rifampicin untersucht und diskutiert. / The therapy of HIV infection requires a combination of several antiretroviral substances accompanying risk factors for drug-drug interactions. Moreover, virus resistance can be promoted by enzyme induction caused by antiretroviral drugs. The aim of the study was to investigate the influences of antiretroviral substances on the expression of cytochrome P450 enzymes: 1A1, 1B1, 3A4 and p-glycoprotein (MDR1) using immortalized cell systems. The protease inhibitors indinavir, nelfinavir, ritonavir and saquinavir induced significantly the regulation of mRNA expression through the aryl hydrocarbon receptor (AhR) and the pregnane-x-receptor (PXR) in a concentration-dependent manner. The nucleoside reverse transcriptase inhibitors zalcitabine, zidovudine and lamivudine and the non-nucleoside reverse transcriptase inhibitor nevirapine showed inductive properties only for the AhR target genes CYP1A1 and CYP1B1.Amprenavir and efavirenz activated the PXR target genes. Potentially effects of the described induction are discussed. In a second part of the work, the molecular mechanisms of the individual varying activity of the CYP3A enzyme were investigated applying an in vivo study. CYP3A4 mRNA expression and rifampicin mediated induction in leucocytes were correlated with systemic enzyme activity under induction and known polymorphisms.
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