subject:(drug AND xenobiotic metabolism)

You searched for subject:(drug AND xenobiotic metabolism). Showing records 1 – 4 of 4 total matches.

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University of Washington

1. Li, Yanfei. Gut-liver axis on biotransformation of environmental chemicals polybrominated diphenyl ethers (PBDEs).

Degree: PhD, 2018, University of Washington

► Polybrominated diphenyl ethers (PBDEs) are flame retardants that are widely used in plastics, rubbers, textiles, furniture and electronic devices. Worrisome levels of PBDEs have been… (more)

▼ Polybrominated diphenyl ethers (PBDEs) are flame retardants that are widely used in plastics, rubbers, textiles, furniture and electronic devices. Worrisome levels of PBDEs have been detected in fatty food, household dust, human blood and breast milk due to their lipophilic and bio-accumulative features. Animal studies, with limited supporting human epidemiology data, have found associations between PBDE exposure and multiple detrimental effects including neurotoxicity, thyroid hormone disorders, and hepatotoxicity such as oxidative stress and cancer. In liver, which is the major organ for xenobiotic biotransformation and nutrient homeostasis, certain PBDE congeners are oxidized by cytochrome P450s (Cyps) to form more toxic metabolites. The gut microbiome has been increasingly recognized as a novel frontier for xenobiotic metabolism, and previous work from our laboratory has demonstrated that lack of a gut microbiome profoundly altered the expression of xenobiotic-processing genes (XPGs) in the liver. However, very little is known regarding the interactions between PBDEs and the gut microbiome, and how such interactions modify the hepatic xenobiotic biotransformation and intermediary metabolism pathways. Therefore, the goal of my dissertation is to utilize multidisciplinary approaches, including germ-free mice, second generation sequencing (RNA-Seq and microbial 16S rRNA sequencing), targeted proteomics (LC-MS), targeted metabolomics (GC-MS for PBDE phenolics and UPLC- MS/MS for bile acids), as well as bioinformatics, to strategically investigate the effect of PBDEs on the gut microbiome in vivo, and further determine how the gut microbiome modulates PBDE-mediated regulation of the hepatic transcriptome and the biotransformation and disposition of PBDEs. To achieve this goal, I exposed nine- week-old male C57BL/6 conventional (CV) and germ-free (GF) mice with vehicle (corn oil, p.o. 10 ml/kg) and the most predominant PBDE congeners, BDE-47 or BDE-99 (100 μmol/kg, p.o.), for four consecutive days. Gut microbiomes were quantified using 16S rRNA sequencing of the large intestinal content (LIC) of CV mice. Both BDE-47 and BDE-99 profoundly decreased the bacterial richness (i.e. α diversity). PBDEs differentially regulated 45 bacterial species, especially an up-regulation of Akkermansia muciniphila and Erysipelotrichacea allobaculum, which are known to have anti- inflammatory and anti-obesity properties. In livers of GF mice, the major BDE-47 hydroxylated metabolite, 5-OH-BDE-47, was higher as compared to livers of CV mice; whereas 4 minor BDE-47 metabolites and 4 minor BDE-99 metabolites were lower. RNA-Seq of the hepatic transcriptome in CV and GF mice showed that the interactions between gut microbiome and PBDEs not only regulated the protein-coding genes (PCGs), but also long non-coding RNAs (lncRNAs), which are increasingly recognized as novel biomarkers for toxicological responses. The absence of gut microbiome sensitized the liver to BDE-99-mediated transcriptional regulation of both PCGs and lncRNAs in GF mice.… Advisors/Committee Members: Cui, Julia Yue (advisor).

Subjects/Keywords: Drug-processing genes; Gut microbiome; Liver; Polybrominated diphenyl ethers; Toxicology; Xenobiotic metabolism; Environmental health; Toxicology; Environmental health

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Li, Y. (2018). Gut-liver axis on biotransformation of environmental chemicals polybrominated diphenyl ethers (PBDEs). (Doctoral Dissertation). University of Washington. Retrieved from http://hdl.handle.net/1773/41774

Chicago Manual of Style (16^th Edition):

Li, Yanfei. “Gut-liver axis on biotransformation of environmental chemicals polybrominated diphenyl ethers (PBDEs).” 2018. Doctoral Dissertation, University of Washington. Accessed February 25, 2021. http://hdl.handle.net/1773/41774.

MLA Handbook (7^th Edition):

Li, Yanfei. “Gut-liver axis on biotransformation of environmental chemicals polybrominated diphenyl ethers (PBDEs).” 2018. Web. 25 Feb 2021.

Vancouver:

Li Y. Gut-liver axis on biotransformation of environmental chemicals polybrominated diphenyl ethers (PBDEs). [Internet] [Doctoral dissertation]. University of Washington; 2018. [cited 2021 Feb 25]. Available from: http://hdl.handle.net/1773/41774.

Council of Science Editors:

Li Y. Gut-liver axis on biotransformation of environmental chemicals polybrominated diphenyl ethers (PBDEs). [Doctoral Dissertation]. University of Washington; 2018. Available from: http://hdl.handle.net/1773/41774

2. CHNG HUI TING. EVALUATION OF ALTERNATIVE IN VIVO AND IN VITRO MODELS FOR DRUG METABOLISM TESTING IN DRUG DISCOVERY.

Degree: 2013, National University of Singapore

URL: http://scholarbank.nus.edu.sg/handle/10635/49381

Subjects/Keywords: xenobiotic; metabolism; zebrafish; hepatocytes; stem cells; drug discovery

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

TING, C. H. (2013). EVALUATION OF ALTERNATIVE IN VIVO AND IN VITRO MODELS FOR DRUG METABOLISM TESTING IN DRUG DISCOVERY. (Thesis). National University of Singapore. Retrieved from http://scholarbank.nus.edu.sg/handle/10635/49381

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

TING, CHNG HUI. “EVALUATION OF ALTERNATIVE IN VIVO AND IN VITRO MODELS FOR DRUG METABOLISM TESTING IN DRUG DISCOVERY.” 2013. Thesis, National University of Singapore. Accessed February 25, 2021. http://scholarbank.nus.edu.sg/handle/10635/49381.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

TING, CHNG HUI. “EVALUATION OF ALTERNATIVE IN VIVO AND IN VITRO MODELS FOR DRUG METABOLISM TESTING IN DRUG DISCOVERY.” 2013. Web. 25 Feb 2021.

Vancouver:

TING CH. EVALUATION OF ALTERNATIVE IN VIVO AND IN VITRO MODELS FOR DRUG METABOLISM TESTING IN DRUG DISCOVERY. [Internet] [Thesis]. National University of Singapore; 2013. [cited 2021 Feb 25]. Available from: http://scholarbank.nus.edu.sg/handle/10635/49381.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

TING CH. EVALUATION OF ALTERNATIVE IN VIVO AND IN VITRO MODELS FOR DRUG METABOLISM TESTING IN DRUG DISCOVERY. [Thesis]. National University of Singapore; 2013. Available from: http://scholarbank.nus.edu.sg/handle/10635/49381

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

3. De Keyser, Joshua Gordon. ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9350

► The human constitutive androstane receptor (CAR) regulates the expression of genes involved in xenobiotic metabolism in the liver. The CAR gene utilizes multiple alternative splicing… (more)

▼ The human constitutive androstane receptor (CAR) regulates the expression of genes involved in xenobiotic metabolism in the liver. The CAR gene utilizes multiple alternative splicing events during pre-mRNA processing, thereby increasing the CAR transcriptome. The work presented in this dissertation focuses on the functional analysis of a prominent human CAR variant, CAR2 that possesses a 4- amino acid insertion in the ligand binding domain. Previous investigations led us to hypothesize that the CAR2 variant is a ligand-activated receptor and possesses a unique ligand binding profile giving rise to novel biological function. We now demonstrate that CAR2 constitutes approximately one-third and one-half of the total CAR transcriptome in human hepatocytes and small intestine, respectively. Further, we identify the common plasticizers, di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP) as highly potent and uniquely selective agonists of CAR2. Results from reporter transactivation assays reveal that DEHP and DiNP activate CAR2 at low nanomolar concentrations. In addition, comparative genomic analysis show that the typical mouse, rat and marmoset models of toxicity can not accurately profile potential human toxicity due to these species inability to generate a CAR2-like transcript. It is also demonstrated that CAR2 possesses an altered ligand pocket that allows for the highly potent and specific activation of the variant by DEHP and DiNP. Further studies show that CAR1 and CAR3 share similar ligand activation profiles; whereas CAR2 responds to most CAR1 and CAR3 ligands as well as a unique subset of chemicals. Finally, it is now shown that meclizine, a human CAR1 inverse-agonist, is a specific agonist of CAR2. A meclizine derived pharmacophore was utilized in a ligand-based virtual screening and identified two novel CAR2 agonists from the NCI chemical database. The results of this dissertation will aid in the development of better models of human CAR activation, give a more complete understanding of the interaction of CAR with xenobiotics, yield novel insight into potential mechanisms of phthalate toxicity and provide the foundation for future studies into the physiologic functions of alternatively spliced variants of CAR. Advisors/Committee Members: Curtis John Omiecinski, Dissertation Advisor/Co-Advisor, Curtis John Omiecinski, Committee Chair/Co-Chair, Reka Z Albert, Committee Member, Adam Bleier Glick, Committee Member, John Patrick Vanden Heuvel, Committee Member.

Subjects/Keywords: phthalates; alternative splicing; constitutive androstane receptor; drug and xenobiotic metabolism; meclizine; nuclear receptors; gene induction

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

De Keyser, J. G. (2009). ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9350

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

De Keyser, Joshua Gordon. “ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY .” 2009. Thesis, Penn State University. Accessed February 25, 2021. https://submit-etda.libraries.psu.edu/catalog/9350.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

De Keyser, Joshua Gordon. “ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY .” 2009. Web. 25 Feb 2021.

Vancouver:

De Keyser JG. ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Feb 25]. Available from: https://submit-etda.libraries.psu.edu/catalog/9350.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

De Keyser JG. ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9350

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Technology, Sydney

4. Pozzoli, Michele. Drug delivery to the nose : formulation, deposition and permeation of poorly soluble drugs.

Degree: 2017, University of Technology, Sydney

URL: http://hdl.handle.net/10453/116418

► The nose, is a promising site to deliver drugs with low oral bioavailability and for treatment of conditions that require a rapid onset of action.… (more)

▼ The nose, is a promising site to deliver drugs with low oral bioavailability and for treatment of conditions that require a rapid onset of action. It is the first option to treat localized diseases such as rhinitis but also it can be used as site to deliver drug systemically. In the future, the number of product administered through the nose it is expected to increase, as more drugs will require an effective route for drug absorption. Hence, while the current characterization of nasal product focus mainly on the physicochemical properties of spray formulations, the biopharmaceutical evaluation of new nasal drug delivery products and formulations will require robust and reliable pre-clinical in vitro models. The first aim of this study was to develop an apparatus able to perform deposition and permeation of nasal formulation at the same time, mimicking so the in vivo process of drug administration. The second aim was the application of this model to the characterization of commercial products and the development of novel formulations. In particular, to provide a physiologically relevant surface and barrier for the deposition and permeation studies, the cell line RPMI 2650 was chosen in order to establish a model of the nasal mucosa. The model was obtained using the air-liquid interface culturing method, in which the upper surface of the cell is exposed to air after the seeding on cell culture insert. The model developed showed production of mucus, expression of xenobiotic transporters similar to primary nasal cells and barrier properties matching those reported in literature for excised human nasal mucosa. The deposition apparatus was produced via 3D printing starting from an expansion chamber proposed by FDA for the determination the aerodynamic particle size of nasal sprays with cascade impactors. The apparatus developed consists of a plastic chamber able to accommodate cell culture inserts on its internal surface. This allows the deposition of aerosolised particles directly onto the surface of the RPMI 2650 cells previously cultured on inserts. The apparatus was validated against FDA glass expansion chamber using three different commercial products: two suspensions and one powder. The powder has shown faster permeation rate across RPMI 2650 cells nasal mucosa model. In conclusion, this work has developed, validated and tested an in vitro method to assess particles deposition and drug permeation in conditions similar to those occurring in vivo and which will be useful for the characterization and development of future nasal products.

Subjects/Keywords: Nasal drug delivery.; Effective route for drug absorption.; Pre-clinical in vitro models for nasal drug delivery.; In vivo process of drug administration.; Novel formulations.; Cell line RPMI 2650.; Xenobiotic transporters.

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pozzoli, M. (2017). Drug delivery to the nose : formulation, deposition and permeation of poorly soluble drugs. (Thesis). University of Technology, Sydney. Retrieved from http://hdl.handle.net/10453/116418

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Pozzoli, Michele. “Drug delivery to the nose : formulation, deposition and permeation of poorly soluble drugs.” 2017. Thesis, University of Technology, Sydney. Accessed February 25, 2021. http://hdl.handle.net/10453/116418.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Pozzoli, Michele. “Drug delivery to the nose : formulation, deposition and permeation of poorly soluble drugs.” 2017. Web. 25 Feb 2021.

Vancouver:

Pozzoli M. Drug delivery to the nose : formulation, deposition and permeation of poorly soluble drugs. [Internet] [Thesis]. University of Technology, Sydney; 2017. [cited 2021 Feb 25]. Available from: http://hdl.handle.net/10453/116418.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Pozzoli M. Drug delivery to the nose : formulation, deposition and permeation of poorly soluble drugs. [Thesis]. University of Technology, Sydney; 2017. Available from: http://hdl.handle.net/10453/116418

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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