The differential cytotoxicity of methotrexate in rat hepatocyte monolayer and spheroid cultures
It is important to assess the usefulness of long-term in vitro liver models for studying chronic toxicity, since acute assays may not reflect the in vivo situation. A potential long-term hepatocyte culture (i.e. liver spheroids) was investigated and compared to primary rat hepatocyte monolayer cultu...
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| Veröffentlicht in: | Toxicology in vitro 2000-10, Vol.14 (5), p.475-485 |
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| container_title | Toxicology in vitro |
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| creator | Walker, T.M Rhodes, P.C Westmoreland, C |
| description | It is important to assess the usefulness of long-term
in vitro liver models for studying chronic toxicity, since acute assays may not reflect the
in vivo situation. A potential long-term hepatocyte culture (i.e. liver spheroids) was investigated and compared to primary rat hepatocyte monolayer cultures following exposure to methotrexate (MTX), a well-documented chronic hepatotoxin. Following up to 7 days' treatment with MTX, cultures were morphologically assessed and assayed for enzyme leakage, intracellular reduced glutathione (GSH) and adenosine triphosphate (ATP). Spheroids maintained higher concentrations of GSH over the 14-day culture and ATP was maintained, but at a concentration not significantly different from monolayer cultures. Treatment of monolayer cultures resulted in concentration-related decreases in GSH and ATP, accompanied by enzyme leakage. In contrast, only ATP was affected following treatment of spheroids for 7 days. Spheroids appeared to be less sensitive to exposure to MTX, when compared with monolayer cultures. This may result from the maintenance of cellular functions, or from the lack of compound penetration into the three-dimensional spheroid structure. Therefore, the usefulness of spheroids to chronic
in vitro toxicity testing may be limited. |
| doi_str_mv | 10.1016/S0887-2333(00)00036-9 |
| format | Article |
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in vitro liver models for studying chronic toxicity, since acute assays may not reflect the
in vivo situation. A potential long-term hepatocyte culture (i.e. liver spheroids) was investigated and compared to primary rat hepatocyte monolayer cultures following exposure to methotrexate (MTX), a well-documented chronic hepatotoxin. Following up to 7 days' treatment with MTX, cultures were morphologically assessed and assayed for enzyme leakage, intracellular reduced glutathione (GSH) and adenosine triphosphate (ATP). Spheroids maintained higher concentrations of GSH over the 14-day culture and ATP was maintained, but at a concentration not significantly different from monolayer cultures. Treatment of monolayer cultures resulted in concentration-related decreases in GSH and ATP, accompanied by enzyme leakage. In contrast, only ATP was affected following treatment of spheroids for 7 days. Spheroids appeared to be less sensitive to exposure to MTX, when compared with monolayer cultures. This may result from the maintenance of cellular functions, or from the lack of compound penetration into the three-dimensional spheroid structure. Therefore, the usefulness of spheroids to chronic
in vitro toxicity testing may be limited.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Alanine Transaminase - metabolism</subject><subject>Animals</subject><subject>Aspartate Aminotransferases - metabolism</subject><subject>Biological and medical sciences</subject><subject>chronic toxicity</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug toxicity and drugs side effects treatment</subject><subject>Glutathione - metabolism</subject><subject>L-Lactate Dehydrogenase - metabolism</subject><subject>Liver - drug effects</subject><subject>Liver - pathology</subject><subject>long-term liver culture</subject><subject>Male</subject><subject>Medical sciences</subject><subject>methotrexate</subject><subject>Methotrexate - toxicity</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>spheroids</subject><subject>Spheroids, Cellular - drug effects</subject><subject>Spheroids, Cellular - enzymology</subject><subject>Spheroids, Cellular - pathology</subject><subject>Toxicity Tests</subject><subject>Toxicity: digestive system</subject><issn>0887-2333</issn><issn>1879-3177</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0E1P7CAUgGFirtHx4yd4w-LG6KIKpaVlZYzxKzFxoa4JhUMG05YRqJn596Iz8bpzdRY8B8iL0BElZ5RQfv5E2rYpSsbYCSGnhBDGC7GFZrRtRMFo0_xBs2-yi_ZifM2obkuyg3YpEZwJXs2QfJ4DNs5aCDAmp3qsV8knv3TapRX2Fg-Q5j4FWKoE2I04qITnsFDJZwl48KPv1QoCVqPBcTGH4J3BeurTFCAeoG2r-giHm7mPXm6un6_uiofH2_ury4dC10ykoi2rtrZAdWUNdKopO50nFYwSwwyvGlUKY7XgtbZdDazrDKjSUmFNPrIl20fH63sXwb9NEJMcXNTQ92oEP0WZg9CGlCTDeg118DEGsHIR3KDCSlIiP8vKr7LyM5skRH6VlSLv_d08MHUDmB9b65QZ_NsAFbXqbVCjdvG_q1rGOc_sYs0g13h3EGTUDkYNxgXQSRrvfvnJB5hkmHI</recordid><startdate>20001001</startdate><enddate>20001001</enddate><creator>Walker, T.M</creator><creator>Rhodes, P.C</creator><creator>Westmoreland, C</creator><general>Elsevier Ltd</general><general>Elsevier Science</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>7U7</scope><scope>C1K</scope></search><sort><creationdate>20001001</creationdate><title>The differential cytotoxicity of methotrexate in rat hepatocyte monolayer and spheroid cultures</title><author>Walker, T.M ; Rhodes, P.C ; Westmoreland, C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c539t-82485fe1c4fdeba72bcdeb19310d3d647a29dfc965cfb5e3bbdea2f19fd7a2f23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Alanine Transaminase - metabolism</topic><topic>Animals</topic><topic>Aspartate Aminotransferases - metabolism</topic><topic>Biological and medical sciences</topic><topic>chronic toxicity</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug toxicity and drugs side effects treatment</topic><topic>Glutathione - metabolism</topic><topic>L-Lactate Dehydrogenase - metabolism</topic><topic>Liver - drug effects</topic><topic>Liver - pathology</topic><topic>long-term liver culture</topic><topic>Male</topic><topic>Medical sciences</topic><topic>methotrexate</topic><topic>Methotrexate - toxicity</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>spheroids</topic><topic>Spheroids, Cellular - drug effects</topic><topic>Spheroids, Cellular - enzymology</topic><topic>Spheroids, Cellular - pathology</topic><topic>Toxicity Tests</topic><topic>Toxicity: digestive system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Walker, T.M</creatorcontrib><creatorcontrib>Rhodes, P.C</creatorcontrib><creatorcontrib>Westmoreland, C</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>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Toxicology in vitro</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Walker, T.M</au><au>Rhodes, P.C</au><au>Westmoreland, C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The differential cytotoxicity of methotrexate in rat hepatocyte monolayer and spheroid cultures</atitle><jtitle>Toxicology in vitro</jtitle><addtitle>Toxicol In Vitro</addtitle><date>2000-10-01</date><risdate>2000</risdate><volume>14</volume><issue>5</issue><spage>475</spage><epage>485</epage><pages>475-485</pages><issn>0887-2333</issn><eissn>1879-3177</eissn><coden>TIVIEQ</coden><abstract>It is important to assess the usefulness of long-term
in vitro liver models for studying chronic toxicity, since acute assays may not reflect the
in vivo situation. A potential long-term hepatocyte culture (i.e. liver spheroids) was investigated and compared to primary rat hepatocyte monolayer cultures following exposure to methotrexate (MTX), a well-documented chronic hepatotoxin. Following up to 7 days' treatment with MTX, cultures were morphologically assessed and assayed for enzyme leakage, intracellular reduced glutathione (GSH) and adenosine triphosphate (ATP). Spheroids maintained higher concentrations of GSH over the 14-day culture and ATP was maintained, but at a concentration not significantly different from monolayer cultures. Treatment of monolayer cultures resulted in concentration-related decreases in GSH and ATP, accompanied by enzyme leakage. In contrast, only ATP was affected following treatment of spheroids for 7 days. Spheroids appeared to be less sensitive to exposure to MTX, when compared with monolayer cultures. This may result from the maintenance of cellular functions, or from the lack of compound penetration into the three-dimensional spheroid structure. Therefore, the usefulness of spheroids to chronic
in vitro toxicity testing may be limited.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>10963964</pmid><doi>10.1016/S0887-2333(00)00036-9</doi><tpages>11</tpages></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Adenosine Triphosphate - metabolism Alanine Transaminase - metabolism Animals Aspartate Aminotransferases - metabolism Biological and medical sciences chronic toxicity Dose-Response Relationship, Drug Drug toxicity and drugs side effects treatment Glutathione - metabolism L-Lactate Dehydrogenase - metabolism Liver - drug effects Liver - pathology long-term liver culture Male Medical sciences methotrexate Methotrexate - toxicity Pharmacology. Drug treatments Rats Rats, Wistar spheroids Spheroids, Cellular - drug effects Spheroids, Cellular - enzymology Spheroids, Cellular - pathology Toxicity Tests Toxicity: digestive system |
| title | The differential cytotoxicity of methotrexate in rat hepatocyte monolayer and spheroid cultures |
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