Formation of methotrexate polyglutamates in rat hepatocytes
Polyglutamate derivatives of [3H]methotrexate (MTX) were detected in freshly isolated rat hepatocytes in suspension within 15 min after exposure to the folate analog. The rate of polyglutamate synthesis remained constant for at least one hr, and the polyglutamate derivatives accounted for an increas...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1979-08, Vol.39 (8), p.2914-2918 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | Gewirtz, D A White, J C Randolph, J K Goldman, I D |
| description | Polyglutamate derivatives of [3H]methotrexate (MTX) were detected in freshly isolated rat hepatocytes in suspension within 15 min after exposure to the folate analog. The rate of polyglutamate synthesis remained constant for at least one hr, and the polyglutamate derivatives accounted for an increasing proportion of the intracellular radiolabel with time. After initial exposure to 1 micron [3H]MTX, polyglutamate derivatives of Mtx continued to be synthesized even after the extracellular [3H]-MTX concentration had been reduced 20-fold. Prolonged exposure of hepatocytes in primary culture to 1 micron [3H]MTX resulted in the formation of longer-chain polyglutamate derivatives of MTX. The present studies demonstrate another important biosynthetic capacity of the freshly isolated hepatocyte and suggest the usefulness of this system for studying the mechanism of, and controlling factors in, the synthesis of polyglutamate derivatives of MTX. The ramifications of the formation of MTX polyglutamates on drug cytotoxicity in general and hepatotoxicity in particular are considered. |
| format | Article |
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The rate of polyglutamate synthesis remained constant for at least one hr, and the polyglutamate derivatives accounted for an increasing proportion of the intracellular radiolabel with time. After initial exposure to 1 micron [3H]MTX, polyglutamate derivatives of Mtx continued to be synthesized even after the extracellular [3H]-MTX concentration had been reduced 20-fold. Prolonged exposure of hepatocytes in primary culture to 1 micron [3H]MTX resulted in the formation of longer-chain polyglutamate derivatives of MTX. The present studies demonstrate another important biosynthetic capacity of the freshly isolated hepatocyte and suggest the usefulness of this system for studying the mechanism of, and controlling factors in, the synthesis of polyglutamate derivatives of MTX. The ramifications of the formation of MTX polyglutamates on drug cytotoxicity in general and hepatotoxicity in particular are considered.</description><identifier>ISSN: 0008-5472</identifier><identifier>PMID: 455278</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; In Vitro Techniques ; Liver - metabolism ; Male ; Methotrexate - analogs & derivatives ; Methotrexate - metabolism ; Peptides - analogs & derivatives ; Polyglutamic Acid - analogs & derivatives ; Polyglutamic Acid - metabolism ; Rats ; Time Factors</subject><ispartof>Cancer research (Chicago, Ill.), 1979-08, Vol.39 (8), p.2914-2918</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/455278$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gewirtz, D A</creatorcontrib><creatorcontrib>White, J C</creatorcontrib><creatorcontrib>Randolph, J K</creatorcontrib><creatorcontrib>Goldman, I D</creatorcontrib><title>Formation of methotrexate polyglutamates in rat hepatocytes</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Polyglutamate derivatives of [3H]methotrexate (MTX) were detected in freshly isolated rat hepatocytes in suspension within 15 min after exposure to the folate analog. The rate of polyglutamate synthesis remained constant for at least one hr, and the polyglutamate derivatives accounted for an increasing proportion of the intracellular radiolabel with time. After initial exposure to 1 micron [3H]MTX, polyglutamate derivatives of Mtx continued to be synthesized even after the extracellular [3H]-MTX concentration had been reduced 20-fold. Prolonged exposure of hepatocytes in primary culture to 1 micron [3H]MTX resulted in the formation of longer-chain polyglutamate derivatives of MTX. The present studies demonstrate another important biosynthetic capacity of the freshly isolated hepatocyte and suggest the usefulness of this system for studying the mechanism of, and controlling factors in, the synthesis of polyglutamate derivatives of MTX. The ramifications of the formation of MTX polyglutamates on drug cytotoxicity in general and hepatotoxicity in particular are considered.</description><subject>Animals</subject><subject>In Vitro Techniques</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Methotrexate - analogs & derivatives</subject><subject>Methotrexate - metabolism</subject><subject>Peptides - analogs & derivatives</subject><subject>Polyglutamic Acid - analogs & derivatives</subject><subject>Polyglutamic Acid - metabolism</subject><subject>Rats</subject><subject>Time Factors</subject><issn>0008-5472</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1979</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNotj09PhDAQxXvw37r6DTz05I2ktB0K8WQ2rmuyiRc9kwEGwQDFtiTy7a3ZPb28eb-ZzLtgGyFEnoA28obdev8dLaQCrtmVBpAm37CnvXUjht5O3LZ8pNDZ4OgXA_HZDuvXsASMOXneT9xh4B3NGGy9xtEdu2xx8HR_1i373L987A7J8f31bfd8TDqp8pBo1WZIhSmkzhRSWoDUIIQyoo7fmFw1AlOjofrHJEgFWQWyatqiggJBqy17PN2dnf1ZyIdy7H1Nw4AT2cWXcTdTKjMRfDiDSzVSU86uH9Gt5ams-gPOgE6a</recordid><startdate>197908</startdate><enddate>197908</enddate><creator>Gewirtz, D A</creator><creator>White, J C</creator><creator>Randolph, J K</creator><creator>Goldman, I D</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>197908</creationdate><title>Formation of methotrexate polyglutamates in rat hepatocytes</title><author>Gewirtz, D A ; White, J C ; Randolph, J K ; Goldman, I D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h238t-43f6ae9792463ae19524500370c051783d0a1745bf6ae252356b52bdf9b59a543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1979</creationdate><topic>Animals</topic><topic>In Vitro Techniques</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Methotrexate - analogs & derivatives</topic><topic>Methotrexate - metabolism</topic><topic>Peptides - analogs & derivatives</topic><topic>Polyglutamic Acid - analogs & derivatives</topic><topic>Polyglutamic Acid - metabolism</topic><topic>Rats</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gewirtz, D A</creatorcontrib><creatorcontrib>White, J C</creatorcontrib><creatorcontrib>Randolph, J K</creatorcontrib><creatorcontrib>Goldman, I D</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gewirtz, D A</au><au>White, J C</au><au>Randolph, J K</au><au>Goldman, I D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Formation of methotrexate polyglutamates in rat hepatocytes</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1979-08</date><risdate>1979</risdate><volume>39</volume><issue>8</issue><spage>2914</spage><epage>2918</epage><pages>2914-2918</pages><issn>0008-5472</issn><abstract>Polyglutamate derivatives of [3H]methotrexate (MTX) were detected in freshly isolated rat hepatocytes in suspension within 15 min after exposure to the folate analog. 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| ispartof | Cancer research (Chicago, Ill.), 1979-08, Vol.39 (8), p.2914-2918 |
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| language | eng |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals In Vitro Techniques Liver - metabolism Male Methotrexate - analogs & derivatives Methotrexate - metabolism Peptides - analogs & derivatives Polyglutamic Acid - analogs & derivatives Polyglutamic Acid - metabolism Rats Time Factors |
| title | Formation of methotrexate polyglutamates in rat hepatocytes |
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