Gastric Parietal Cell Atrophy and Depletion after Administration of a Sphingosine-1-Phosphate 1 Inhibitor
Sphingosine-1-phosphate (S1P) is a major bioactive phospholipid, which binds to and activates a family of five G-protein-coupled receptors designated as S1P 1 (S1P1) through S1P5. The S1P1 receptor subtype, expressed primarily on lymphocytes, is known to play a critical role in the regulation of lym...
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| Veröffentlicht in: | Toxicologic pathology 2014-01, Vol.42 (1), p.118-123 |
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| creator | Radi, Zaher A. Vogel, Mark W. |
| description | Sphingosine-1-phosphate (S1P) is a major bioactive phospholipid, which binds to and activates a family of five G-protein-coupled receptors designated as S1P 1 (S1P1) through S1P5. The S1P1 receptor subtype, expressed primarily on lymphocytes, is known to play a critical role in the regulation of lymphocyte trafficking. S1P1 inhibitors result in the inhibition of lymphoid cell trafficking and are of interest to treat various inflammatory conditions. In this study, we describe a gastric finding associated with oral gavage administration of a small molecule S1P1 inhibitor to Sprague-Dawley rats. Rats were administered an S1P1 inhibitor once daily for 4 weeks and necropsies were conducted at the end of the dosing phase, and clinical pathology and histopathologic examination were performed. Lymphopenia and changes in lymphoid tissues were noted and were consistent with the pharmacodynamic effects for S1P1 inhibitory action. Histopathologic examination of the stomach revealed atrophy and depletion of gastric parietal cells in the glandular portion of the stomach. There are no literature data to suggest that this gastric effect is related to S1P1 pharmacology. Therefore, the mechanism of the observed gastric lesion is likely chemotype mediated. |
| doi_str_mv | 10.1177/0192623313506790 |
| format | Article |
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The S1P1 receptor subtype, expressed primarily on lymphocytes, is known to play a critical role in the regulation of lymphocyte trafficking. S1P1 inhibitors result in the inhibition of lymphoid cell trafficking and are of interest to treat various inflammatory conditions. In this study, we describe a gastric finding associated with oral gavage administration of a small molecule S1P1 inhibitor to Sprague-Dawley rats. Rats were administered an S1P1 inhibitor once daily for 4 weeks and necropsies were conducted at the end of the dosing phase, and clinical pathology and histopathologic examination were performed. Lymphopenia and changes in lymphoid tissues were noted and were consistent with the pharmacodynamic effects for S1P1 inhibitory action. Histopathologic examination of the stomach revealed atrophy and depletion of gastric parietal cells in the glandular portion of the stomach. There are no literature data to suggest that this gastric effect is related to S1P1 pharmacology. Therefore, the mechanism of the observed gastric lesion is likely chemotype mediated.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Atrophy</subject><subject>Female</subject><subject>Lymphocytes - drug effects</subject><subject>Lymphocytes - metabolism</subject><subject>Lymphoid Tissue - pathology</subject><subject>Lysophospholipids - antagonists & inhibitors</subject><subject>Male</subject><subject>Parietal Cells, Gastric - drug effects</subject><subject>Parietal Cells, Gastric - pathology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Lysosphingolipid - genetics</subject><subject>Receptors, Lysosphingolipid - metabolism</subject><subject>Sphingosine - analogs & derivatives</subject><subject>Sphingosine - antagonists & inhibitors</subject><subject>Stomach - pathology</subject><issn>0192-6233</issn><issn>1533-1601</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUFr3DAQhUVJ6G7S3nsKOubiZMayJeu4bNtkYSGBtmcjW-NYi9dyJO0h_77ebNpDoZDTwMz3Hsx7jH1BuEFU6hZQ5zIXAkUJUmn4wJZYCpGhBDxjy-M5O94X7CLGHQBWWMBHtsgLVFWp8iVzdyam4Fr-aIKjZAa-pmHgqxT81L9wM1r-laaBkvMjN12iwFd270Y3q8zr0nfc8B9T78YnH91IGWaPvY9TbxJx5Juxd41LPnxi550ZIn1-m5fs1_dvP9f32fbhbrNebbNWyDJlhWxa7FBWVHS2QVEYFFYoi1oQUN4oaCAvQJICKzXopmw7SRqUtNqaRolLdn3ynYJ_PlBM9d7Fdn7KjOQPscZCy6rKS1m9BwWlclnoGYUT2gYfY6CunoLbm_BSI9THLup_u5glV2_uh2ZP9q_gT_gzkJ2AaJ6o3vlDGOdg_m_4G5O0kCE</recordid><startdate>201401</startdate><enddate>201401</enddate><creator>Radi, Zaher A.</creator><creator>Vogel, Mark W.</creator><general>SAGE Publications</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>201401</creationdate><title>Gastric Parietal Cell Atrophy and Depletion after Administration of a Sphingosine-1-Phosphate 1 Inhibitor</title><author>Radi, Zaher A. ; Vogel, Mark W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c365t-46bc1f168e4fdb134a13d37d193e0e2b70b02406e70d6909b5cf6e9076d9dab73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Atrophy</topic><topic>Female</topic><topic>Lymphocytes - drug effects</topic><topic>Lymphocytes - metabolism</topic><topic>Lymphoid Tissue - pathology</topic><topic>Lysophospholipids - antagonists & inhibitors</topic><topic>Male</topic><topic>Parietal Cells, Gastric - drug effects</topic><topic>Parietal Cells, Gastric - pathology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Lysosphingolipid - genetics</topic><topic>Receptors, Lysosphingolipid - metabolism</topic><topic>Sphingosine - analogs & derivatives</topic><topic>Sphingosine - antagonists & inhibitors</topic><topic>Stomach - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Radi, Zaher A.</creatorcontrib><creatorcontrib>Vogel, Mark W.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Toxicologic pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Radi, Zaher A.</au><au>Vogel, Mark W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gastric Parietal Cell Atrophy and Depletion after Administration of a Sphingosine-1-Phosphate 1 Inhibitor</atitle><jtitle>Toxicologic pathology</jtitle><addtitle>Toxicol Pathol</addtitle><date>2014-01</date><risdate>2014</risdate><volume>42</volume><issue>1</issue><spage>118</spage><epage>123</epage><pages>118-123</pages><issn>0192-6233</issn><eissn>1533-1601</eissn><abstract>Sphingosine-1-phosphate (S1P) is a major bioactive phospholipid, which binds to and activates a family of five G-protein-coupled receptors designated as S1P 1 (S1P1) through S1P5. The S1P1 receptor subtype, expressed primarily on lymphocytes, is known to play a critical role in the regulation of lymphocyte trafficking. S1P1 inhibitors result in the inhibition of lymphoid cell trafficking and are of interest to treat various inflammatory conditions. In this study, we describe a gastric finding associated with oral gavage administration of a small molecule S1P1 inhibitor to Sprague-Dawley rats. Rats were administered an S1P1 inhibitor once daily for 4 weeks and necropsies were conducted at the end of the dosing phase, and clinical pathology and histopathologic examination were performed. Lymphopenia and changes in lymphoid tissues were noted and were consistent with the pharmacodynamic effects for S1P1 inhibitory action. Histopathologic examination of the stomach revealed atrophy and depletion of gastric parietal cells in the glandular portion of the stomach. There are no literature data to suggest that this gastric effect is related to S1P1 pharmacology. Therefore, the mechanism of the observed gastric lesion is likely chemotype mediated.</abstract><cop>Los Angeles, CA</cop><pub>SAGE Publications</pub><pmid>24178572</pmid><doi>10.1177/0192623313506790</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Toxicologic pathology, 2014-01, Vol.42 (1), p.118-123 |
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| subjects | Administration, Oral Animals Atrophy Female Lymphocytes - drug effects Lymphocytes - metabolism Lymphoid Tissue - pathology Lysophospholipids - antagonists & inhibitors Male Parietal Cells, Gastric - drug effects Parietal Cells, Gastric - pathology Rats Rats, Sprague-Dawley Receptors, Lysosphingolipid - genetics Receptors, Lysosphingolipid - metabolism Sphingosine - analogs & derivatives Sphingosine - antagonists & inhibitors Stomach - pathology |
| title | Gastric Parietal Cell Atrophy and Depletion after Administration of a Sphingosine-1-Phosphate 1 Inhibitor |
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