We study regulation of the human pregnane X receptor (hPXR) and constitutive androstane receptor (hCAR) and their roles in drug disposition. Both hPXR and hCAR: 1) are nuclear receptors modulated by many structurally diverse chemicals, either directly via receptor binding or indirectly via signaling cross-talk; 2) transcriptionally regulate drug metabolizing enzymes and transporters to control xenobiotic disposition and endobiotic homeostasis; 3) are implicated not only in drug effects but also in the development of human diseases, such as diabetes and cancer; 4)form heterodimers with retinoid X receptor to bind the promoters of their target genes, which may be unique to a receptor or overlap; 5) are affected by coactivators and corepressors; and 6) interact similarly or differently with various regulatory partners, including chemicals, DNA elements, proteins, and microRNAs. Several key gaps remain in our overall understanding of hPXR and hCAR regulation and function. First, hPXR and hCAR not only regulate drug metabolism but also interact with other signaling molecules, regulating or being regulated by them. Despite ongoing progress, we lack a complete picture of hPXR and hCAR interactions with their regulators, and of the regulation by and regulation of these interactions. Second, a systematic effort is needed to develop chemical tools to dissect hPXR and hCAR regulation in detail. Our two long-term goals are to comprehensively examine the regulation of hPXR and hCAR and its implications for drug disposition and human diseases, and to develop chemical tools to elucidate hPXR and hCAR regulation and its potential application for preventing drug toxicity and improving bioavailability. We have advanced toward these goals by discovering mechanisms that regulate hPXR and hCAR, including protein-protein interactions, post-translational modification and post-transcriptional regulation (microRNAs), and by developing the novel hPXR antagonist SPA70, the hCAR inverse agonist CINPA1, and their analogs. We will meet 3 challenges during the funding period: (1) Illustrate how hPXR and hCAR regulate drug toxicity and resistance by examining to what extent SPA70 prevents drug toxicity and CINPA1 reduces drug resistance and determining the underlying mechanisms. (2) Define the fundamental mechanism responsible for the action of hPXR antagonists and hCAR inverse agonists by obtaining the co-crystal structures of hPXR with antagonist (SPA70) and hCAR with inverse agonist (CINPA1) and carrying out structural-functional analysis. (3) Better understand hPXR and hCAR protein-protein interaction networks and reciprocal regulatory effects, starting by examining how signaling cross-talk between genotoxic- and xenobiotic-responsive pathways reduces the effect of genotoxic stress. Together, our findings will provide not only a broader comprehension of the regulation of hPXR and hCAR and how they control the human body's response to xenobiotic s and endobiotics, but also novel modulators of hPXR and hCAR for further interrogating their broad cellular function, and as leads for therapies to prevent drug toxicity and improve drug bioavailability.
We propose to study the role of xenobiotic receptors in drug toxicity and drug resistance, the leading causes of treatment failure. We will determine the mechanism and effects of two novel compounds on preventing drug toxicity, increasing intracellular drug accumulation and re-sensitizing drug-resistant cells to chemotherapeutic agents. The results of our proposed studies will illustrate how drugs cause toxic effects and drug resistance, and identify potential therapeutic approach to prevent the toxicity, reverse drug resistance and improve treatment efficacy.
|Teitz, Tal; Fang, Jie; Goktug, Asli N et al. (2018) CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. J Exp Med 215:1187-1203|
|Buchman, Cameron D; Chai, Sergio C; Chen, Taosheng (2018) A current structural perspective on PXR and CAR in drug metabolism. Expert Opin Drug Metab Toxicol 14:635-647|
|Cherian, Milu T; Chai, Sergio C; Wright, William C et al. (2018) CINPA1 binds directly to constitutive androstane receptor and inhibits its activity. Biochem Pharmacol 152:211-223|
|Li, Yanfeng; Bakke, Jesse; Finkelstein, David et al. (2018) HNRNPH1 is required for rhabdomyosarcoma cell growth and survival. Oncogenesis 7:9|
|Lin, Wenwei; Chen, Taosheng (2018) Using TR-FRET to Investigate Protein-Protein Interactions: A Case Study of PXR-Coregulator Interaction. Adv Protein Chem Struct Biol 110:31-63|
|Oladimeji, Peter O; Chen, Taosheng (2018) PXR: More Than Just a Master Xenobiotic Receptor. Mol Pharmacol 93:119-127|
|Oladimeji, Peter O; Wright, William C; Wu, Jing et al. (2018) RNA interference screen identifies NAA10 as a regulator of PXR transcription. Biochem Pharmacol 160:92-109|
|Lin, Wenwei; Wang, Yue-Ming; Chai, Sergio C et al. (2017) SPA70 is a potent antagonist of human pregnane X receptor. Nat Commun 8:741|
|Lin, Wenwei; Goktug, Asli N; Wu, Jing et al. (2017) High-Throughput Screening Identifies 1,4,5-Substituted 1,2,3-Triazole Analogs as Potent and Specific Antagonists of Pregnane X Receptor. Assay Drug Dev Technol 15:383-394|
|Lolodi, Ogheneochukome; Wang, Yue-Ming; Wright, William C et al. (2017) Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery. Curr Drug Metab 18:1095-1105|
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