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Penn State University

1. 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

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 (6th 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 (16th 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 (7th 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

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