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Rat liver treated by PCN

ABSTRACT: The combination analyses of transcriptomics, proteomics, phosphoproteomics, and metabolomics in rat liver after repeated oral doses of PXR agonist, PCN, for 7 days were conducted to understand the roles for PXR on non-genotoxic signaling and energy homeostasis. mRNA and proteins in homogenate supernatant, membrane, and cytosolic fractions prepared from the liver were analyzed.

ORGANISM(S): Rattus Rattus (black Rat)

SUBMITTER: Sumio Ohtsuki

PROVIDER: PXD006305 | JPOST Repository | Mon Jan 01 00:00:00 GMT 2018

REPOSITORIES: jPOST

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Dataset's files

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			Action	DRS
	Cytosol_Control.wiff	Wiff
	Cytosol_Control.wiff.scan	Wiff
	Cytosol_PCN.wiff	Wiff
	Cytosol_PCN.wiff.scan	Wiff
	Microsome_Control_IDA1.wiff	Wiff

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Publications

Combining Genomics To Identify the Pathways of Post-Transcriptional Nongenotoxic Signaling and Energy Homeostasis in Livers of Rats Treated with the Pregnane X Receptor Agonist, Pregnenolone Carbonitrile.

Nagahori Hirohisa H Nakamura Kenji K Sumida Kayo K Ito Shingo S Ohtsuki Sumio S

Journal of proteome research 20170906 10

Transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses were combined to determine the role of pregnane X receptor (PXR) in nongenotoxic signaling and energy homeostasis in liver after rats were repeatedly orally dosed with the PXR agonist pregnenolone carbonitrile (PCN) for 7 days. Analyses of mRNAs and proteins in the supernatant, membrane, and cytosolic fractions of enlarged liver homogenates showed diverse expression profiles. Gene set enrichment analysis showed that the synchr ...[more]

PMID: 28825834

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Project description:IMA-08401 (C2) represents a novel AHR agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Although both compounds produce an identical AHR-active metabolite, IMA-06201 (DELAQ) in vivo, C2 generates it to a far greater degree. SAHRMs have been proposed as therapeutic options for autoimmune disorders, including multiple sclerosis. So far, clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, more research is required due to the functional resemblance of these compounds to the highly toxic AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we report transcriptomic profiling of rat liver following acute (single-dose) and sub-acute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to high doses of C2. Exposure to C2 leads to activation of the AHR, as shown by changes in mRNA abundance of the prototypical AHR-response gene Cyp1a1. We identify a heightened response early after exposure (1 day) that drops off considerably by day 10. Acute exposure to C2 produces a significant immune response, with a focus on antiviral and antibacterial responses that highlights the dual effects of AhR agonists as immunomodulators. Sub-acute exposure leads to an increase in oxidative stress in the liver, the consequences of which require further study on sensitive tissues, such as the CNS and immune system which may be compromised in patients with the target autoimmune disorders.

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