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Glycyrrhizin and some analogues induce growth of primary cultured adult rat hepatocytes via epidermal growth factor receptors
We investigated the effects of glycyrrhizin (GL-1) and some analogues on DNA synthesis and proliferation in serum-free primary cultures of adult rat hepatocytes. The hepatocytes underwent DNA synthesis and proliferation in response to GL-1 and some analogues. The effects of these agents occurred in...
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| Published in: | European journal of pharmacology 2001-11, Vol.431 (2), p.151-161 |
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| cites | cdi_FETCH-LOGICAL-c391t-2169781c357a183d06a274eb558908cdc6a4cf0dff1bd22cf21bb7751569a0f23 |
| container_end_page | 161 |
| container_issue | 2 |
| container_start_page | 151 |
| container_title | European journal of pharmacology |
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| creator | Kimura, Mitsutoshi Inoue, Hideo Hirabayashi, Kazuhiro Natsume, Hideshi Ogihara, Masahiko |
| description | We investigated the effects of glycyrrhizin (GL-1) and some analogues on DNA synthesis and proliferation in serum-free primary cultures of adult rat hepatocytes. The hepatocytes underwent DNA synthesis and proliferation in response to GL-1 and some analogues. The effects of these agents occurred in a time- and dose-dependent manner. The proliferative potency as judged by half-maximal effective concentrations was in the following order: 18-β-
H-glycyrrhetinic acid (GL-3; 4.5×10
−9 M) |
| doi_str_mv | 10.1016/S0014-2999(01)01424-8 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_72316816</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0014299901014248</els_id><sourcerecordid>72316816</sourcerecordid><originalsourceid>FETCH-LOGICAL-c391t-2169781c357a183d06a274eb558908cdc6a4cf0dff1bd22cf21bb7751569a0f23</originalsourceid><addsrcrecordid>eNqFkE1vFSEUhonR2NvqT9Cw0ehilMN8wcqYRqtJExfqmjBw6MXMDCMwba6J_13aO9qlK97F857DeQh5BuwNMOjefmUMmopLKV8xeF0ybyrxgOxA9LJiPfCHZPcPOSGnKf1gjLWSt4_JCUDPRcNhR35fjAdziHHvf_mZ6tnSFCYsQY_hasVE_WxXg_Qqhpu8p8HRJfpJxwM165jXiJZqWxKNOtM9LjoHc8ild-01xcVbjJMe_9adNjlEGtHgUkJ6Qh45PSZ8ur1n5PvHD9_OP1WXXy4-n7-_rEwtIVccOtkLMHXbaxC1ZZ3mfYND2wrJhLGm041xzDoHg-XcOA7D0PcttJ3UzPH6jLw8zl1i-FmuymryyeA46hnDmlTPa-gEdAVsj6CJIaWITm3nKmDq1ru6865upSoG6s67EqX3fFuwDhPa-9YmugAvNkAno0cX9Wx8uucaYBJqVrh3Rw6LjmuPUSXjcTZofbGWlQ3-P1_5A6Yvoec</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>72316816</pqid></control><display><type>article</type><title>Glycyrrhizin and some analogues induce growth of primary cultured adult rat hepatocytes via epidermal growth factor receptors</title><source>ScienceDirect Journals</source><creator>Kimura, Mitsutoshi ; Inoue, Hideo ; Hirabayashi, Kazuhiro ; Natsume, Hideshi ; Ogihara, Masahiko</creator><creatorcontrib>Kimura, Mitsutoshi ; Inoue, Hideo ; Hirabayashi, Kazuhiro ; Natsume, Hideshi ; Ogihara, Masahiko</creatorcontrib><description>We investigated the effects of glycyrrhizin (GL-1) and some analogues on DNA synthesis and proliferation in serum-free primary cultures of adult rat hepatocytes. The hepatocytes underwent DNA synthesis and proliferation in response to GL-1 and some analogues. The effects of these agents occurred in a time- and dose-dependent manner. The proliferative potency as judged by half-maximal effective concentrations was in the following order: 18-β-
H-glycyrrhetinic acid (GL-3; 4.5×10
−9 M)<18-β-
H-glycyrrhizin (GL-1; 4.4×10
−8 M)<18-α-
H-glycyrrhetinic acid (GL-6; 6.0×10
−8 M). The analogue 18-α-
H-glycyrrhetinic acid 3-
O-β-
d-monoglucuronide (GL-5; 1.0×10
−7 M) weakly stimulated hepatocyte DNA synthesis and proliferation, whereas 18-α-
H-glycyrrhizin (GL-4) and 18-β-
H-glycyrrhetinic acid 3-
O-β-
d-monoglucuronide (GL-2) did not. The growth-promoting effects of GL-1, GL-3 and GL-6 were significantly inhibited at higher initial plating densities (7.0×10
4 and 10×10
4 cells/cm
2). A monoclonal antibody against epidermal growth factor (EGF) receptor (1–100 ng/ml), but not that against EGF (1–100 ng/ml), dose-dependently inhibited glycyrrhizin- and analogue-induced hepatocyte DNA synthesis and proliferation. Specific inhibitors of growth-related signal transducers, such as genistein, PD98059 (2′-amino-3′-methoxyflavone) and rapamycin, completely blocked glycyrrhizin- and analogue-induced hepatocyte DNA synthesis and proliferation. Treatment of hepatocytes with GL-1, GL-3 and GL-6 rapidly stimulated tyrosine phosphorylation of the EGF receptor and p42 MAP kinase, which were inhibited by genistein and PD98059, respectively. These results suggest that glycyrrhizin and some analogues are primary hepatocyte mitogens that bind to EGF receptors and subsequently stimulate the receptor tyrosine kinase/mitogen-activated protein kinase pathway to induce hepatocyte DNA synthesis and proliferation.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/S0014-2999(01)01424-8</identifier><identifier>PMID: 11728421</identifier><identifier>CODEN: EJPHAZ</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Adenylyl Cyclase Inhibitors ; Adult ; Animals ; Antibodies, Monoclonal - immunology ; Biological and medical sciences ; Cell Count ; Cell Division - drug effects ; Cells, Cultured ; Cyclic AMP - metabolism ; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors ; DNA - biosynthesis ; DNA synthesis ; Dose-Response Relationship, Drug ; ErbB Receptors - agonists ; ErbB Receptors - immunology ; ErbB Receptors - metabolism ; General pharmacology ; Glycyrrhizic Acid - analogs & derivatives ; Glycyrrhizic Acid - chemistry ; Glycyrrhizic Acid - pharmacology ; Glycyrrhizin ; Hepatocyte ; Hepatocytes - drug effects ; Liver Regeneration ; Male ; Medical sciences ; Mitogen-Activated Protein Kinase 1 - metabolism ; Molecular Structure ; Pharmacognosy. Homeopathy. Health food ; Pharmacology. Drug treatments ; Phosphorylation ; Primary culture ; Proliferation ; rat ; Rats ; Rats, Wistar ; Signal Transduction - drug effects ; Time Factors</subject><ispartof>European journal of pharmacology, 2001-11, Vol.431 (2), p.151-161</ispartof><rights>2001 Elsevier Science B.V.</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-2169781c357a183d06a274eb558908cdc6a4cf0dff1bd22cf21bb7751569a0f23</citedby><cites>FETCH-LOGICAL-c391t-2169781c357a183d06a274eb558908cdc6a4cf0dff1bd22cf21bb7751569a0f23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14109130$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11728421$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kimura, Mitsutoshi</creatorcontrib><creatorcontrib>Inoue, Hideo</creatorcontrib><creatorcontrib>Hirabayashi, Kazuhiro</creatorcontrib><creatorcontrib>Natsume, Hideshi</creatorcontrib><creatorcontrib>Ogihara, Masahiko</creatorcontrib><title>Glycyrrhizin and some analogues induce growth of primary cultured adult rat hepatocytes via epidermal growth factor receptors</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>We investigated the effects of glycyrrhizin (GL-1) and some analogues on DNA synthesis and proliferation in serum-free primary cultures of adult rat hepatocytes. The hepatocytes underwent DNA synthesis and proliferation in response to GL-1 and some analogues. The effects of these agents occurred in a time- and dose-dependent manner. The proliferative potency as judged by half-maximal effective concentrations was in the following order: 18-β-
H-glycyrrhetinic acid (GL-3; 4.5×10
−9 M)<18-β-
H-glycyrrhizin (GL-1; 4.4×10
−8 M)<18-α-
H-glycyrrhetinic acid (GL-6; 6.0×10
−8 M). The analogue 18-α-
H-glycyrrhetinic acid 3-
O-β-
d-monoglucuronide (GL-5; 1.0×10
−7 M) weakly stimulated hepatocyte DNA synthesis and proliferation, whereas 18-α-
H-glycyrrhizin (GL-4) and 18-β-
H-glycyrrhetinic acid 3-
O-β-
d-monoglucuronide (GL-2) did not. The growth-promoting effects of GL-1, GL-3 and GL-6 were significantly inhibited at higher initial plating densities (7.0×10
4 and 10×10
4 cells/cm
2). A monoclonal antibody against epidermal growth factor (EGF) receptor (1–100 ng/ml), but not that against EGF (1–100 ng/ml), dose-dependently inhibited glycyrrhizin- and analogue-induced hepatocyte DNA synthesis and proliferation. Specific inhibitors of growth-related signal transducers, such as genistein, PD98059 (2′-amino-3′-methoxyflavone) and rapamycin, completely blocked glycyrrhizin- and analogue-induced hepatocyte DNA synthesis and proliferation. Treatment of hepatocytes with GL-1, GL-3 and GL-6 rapidly stimulated tyrosine phosphorylation of the EGF receptor and p42 MAP kinase, which were inhibited by genistein and PD98059, respectively. These results suggest that glycyrrhizin and some analogues are primary hepatocyte mitogens that bind to EGF receptors and subsequently stimulate the receptor tyrosine kinase/mitogen-activated protein kinase pathway to induce hepatocyte DNA synthesis and proliferation.</description><subject>Adenylyl Cyclase Inhibitors</subject><subject>Adult</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Biological and medical sciences</subject><subject>Cell Count</subject><subject>Cell Division - drug effects</subject><subject>Cells, Cultured</subject><subject>Cyclic AMP - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors</subject><subject>DNA - biosynthesis</subject><subject>DNA synthesis</subject><subject>Dose-Response Relationship, Drug</subject><subject>ErbB Receptors - agonists</subject><subject>ErbB Receptors - immunology</subject><subject>ErbB Receptors - metabolism</subject><subject>General pharmacology</subject><subject>Glycyrrhizic Acid - analogs & derivatives</subject><subject>Glycyrrhizic Acid - chemistry</subject><subject>Glycyrrhizic Acid - pharmacology</subject><subject>Glycyrrhizin</subject><subject>Hepatocyte</subject><subject>Hepatocytes - drug effects</subject><subject>Liver Regeneration</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Molecular Structure</subject><subject>Pharmacognosy. Homeopathy. Health food</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphorylation</subject><subject>Primary culture</subject><subject>Proliferation</subject><subject>rat</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Signal Transduction - drug effects</subject><subject>Time Factors</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><recordid>eNqFkE1vFSEUhonR2NvqT9Cw0ehilMN8wcqYRqtJExfqmjBw6MXMDCMwba6J_13aO9qlK97F857DeQh5BuwNMOjefmUMmopLKV8xeF0ybyrxgOxA9LJiPfCHZPcPOSGnKf1gjLWSt4_JCUDPRcNhR35fjAdziHHvf_mZ6tnSFCYsQY_hasVE_WxXg_Qqhpu8p8HRJfpJxwM165jXiJZqWxKNOtM9LjoHc8ild-01xcVbjJMe_9adNjlEGtHgUkJ6Qh45PSZ8ur1n5PvHD9_OP1WXXy4-n7-_rEwtIVccOtkLMHXbaxC1ZZ3mfYND2wrJhLGm041xzDoHg-XcOA7D0PcttJ3UzPH6jLw8zl1i-FmuymryyeA46hnDmlTPa-gEdAVsj6CJIaWITm3nKmDq1ru6865upSoG6s67EqX3fFuwDhPa-9YmugAvNkAno0cX9Wx8uucaYBJqVrh3Rw6LjmuPUSXjcTZofbGWlQ3-P1_5A6Yvoec</recordid><startdate>20011116</startdate><enddate>20011116</enddate><creator>Kimura, Mitsutoshi</creator><creator>Inoue, Hideo</creator><creator>Hirabayashi, Kazuhiro</creator><creator>Natsume, Hideshi</creator><creator>Ogihara, Masahiko</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><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></search><sort><creationdate>20011116</creationdate><title>Glycyrrhizin and some analogues induce growth of primary cultured adult rat hepatocytes via epidermal growth factor receptors</title><author>Kimura, Mitsutoshi ; Inoue, Hideo ; Hirabayashi, Kazuhiro ; Natsume, Hideshi ; Ogihara, Masahiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-2169781c357a183d06a274eb558908cdc6a4cf0dff1bd22cf21bb7751569a0f23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Adenylyl Cyclase Inhibitors</topic><topic>Adult</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Biological and medical sciences</topic><topic>Cell Count</topic><topic>Cell Division - drug effects</topic><topic>Cells, Cultured</topic><topic>Cyclic AMP - metabolism</topic><topic>Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors</topic><topic>DNA - biosynthesis</topic><topic>DNA synthesis</topic><topic>Dose-Response Relationship, Drug</topic><topic>ErbB Receptors - agonists</topic><topic>ErbB Receptors - immunology</topic><topic>ErbB Receptors - metabolism</topic><topic>General pharmacology</topic><topic>Glycyrrhizic Acid - analogs & derivatives</topic><topic>Glycyrrhizic Acid - chemistry</topic><topic>Glycyrrhizic Acid - pharmacology</topic><topic>Glycyrrhizin</topic><topic>Hepatocyte</topic><topic>Hepatocytes - drug effects</topic><topic>Liver Regeneration</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Molecular Structure</topic><topic>Pharmacognosy. Homeopathy. Health food</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphorylation</topic><topic>Primary culture</topic><topic>Proliferation</topic><topic>rat</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Signal Transduction - drug effects</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kimura, Mitsutoshi</creatorcontrib><creatorcontrib>Inoue, Hideo</creatorcontrib><creatorcontrib>Hirabayashi, Kazuhiro</creatorcontrib><creatorcontrib>Natsume, Hideshi</creatorcontrib><creatorcontrib>Ogihara, Masahiko</creatorcontrib><collection>Pascal-Francis</collection><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><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kimura, Mitsutoshi</au><au>Inoue, Hideo</au><au>Hirabayashi, Kazuhiro</au><au>Natsume, Hideshi</au><au>Ogihara, Masahiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glycyrrhizin and some analogues induce growth of primary cultured adult rat hepatocytes via epidermal growth factor receptors</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2001-11-16</date><risdate>2001</risdate><volume>431</volume><issue>2</issue><spage>151</spage><epage>161</epage><pages>151-161</pages><issn>0014-2999</issn><eissn>1879-0712</eissn><coden>EJPHAZ</coden><abstract>We investigated the effects of glycyrrhizin (GL-1) and some analogues on DNA synthesis and proliferation in serum-free primary cultures of adult rat hepatocytes. The hepatocytes underwent DNA synthesis and proliferation in response to GL-1 and some analogues. The effects of these agents occurred in a time- and dose-dependent manner. The proliferative potency as judged by half-maximal effective concentrations was in the following order: 18-β-
H-glycyrrhetinic acid (GL-3; 4.5×10
−9 M)<18-β-
H-glycyrrhizin (GL-1; 4.4×10
−8 M)<18-α-
H-glycyrrhetinic acid (GL-6; 6.0×10
−8 M). The analogue 18-α-
H-glycyrrhetinic acid 3-
O-β-
d-monoglucuronide (GL-5; 1.0×10
−7 M) weakly stimulated hepatocyte DNA synthesis and proliferation, whereas 18-α-
H-glycyrrhizin (GL-4) and 18-β-
H-glycyrrhetinic acid 3-
O-β-
d-monoglucuronide (GL-2) did not. The growth-promoting effects of GL-1, GL-3 and GL-6 were significantly inhibited at higher initial plating densities (7.0×10
4 and 10×10
4 cells/cm
2). A monoclonal antibody against epidermal growth factor (EGF) receptor (1–100 ng/ml), but not that against EGF (1–100 ng/ml), dose-dependently inhibited glycyrrhizin- and analogue-induced hepatocyte DNA synthesis and proliferation. Specific inhibitors of growth-related signal transducers, such as genistein, PD98059 (2′-amino-3′-methoxyflavone) and rapamycin, completely blocked glycyrrhizin- and analogue-induced hepatocyte DNA synthesis and proliferation. Treatment of hepatocytes with GL-1, GL-3 and GL-6 rapidly stimulated tyrosine phosphorylation of the EGF receptor and p42 MAP kinase, which were inhibited by genistein and PD98059, respectively. These results suggest that glycyrrhizin and some analogues are primary hepatocyte mitogens that bind to EGF receptors and subsequently stimulate the receptor tyrosine kinase/mitogen-activated protein kinase pathway to induce hepatocyte DNA synthesis and proliferation.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>11728421</pmid><doi>10.1016/S0014-2999(01)01424-8</doi><tpages>11</tpages></addata></record> |
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| ispartof | European journal of pharmacology, 2001-11, Vol.431 (2), p.151-161 |
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| subjects | Adenylyl Cyclase Inhibitors Adult Animals Antibodies, Monoclonal - immunology Biological and medical sciences Cell Count Cell Division - drug effects Cells, Cultured Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors DNA - biosynthesis DNA synthesis Dose-Response Relationship, Drug ErbB Receptors - agonists ErbB Receptors - immunology ErbB Receptors - metabolism General pharmacology Glycyrrhizic Acid - analogs & derivatives Glycyrrhizic Acid - chemistry Glycyrrhizic Acid - pharmacology Glycyrrhizin Hepatocyte Hepatocytes - drug effects Liver Regeneration Male Medical sciences Mitogen-Activated Protein Kinase 1 - metabolism Molecular Structure Pharmacognosy. Homeopathy. Health food Pharmacology. Drug treatments Phosphorylation Primary culture Proliferation rat Rats Rats, Wistar Signal Transduction - drug effects Time Factors |
| title | Glycyrrhizin and some analogues induce growth of primary cultured adult rat hepatocytes via epidermal growth factor receptors |
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