Humanization of Excretory Pathway in Chimeric Mice with Humanized Liver
The liver of a chimeric urokinase-type plasminogen activator (uPA)+/+/severe combined immunodeficient (SCID) mouse line recently established in Japan could be replaced by more than 80% with human hepatocytes. We previously reported that the chimeric mice with humanized liver could be useful as a hum...
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| Veröffentlicht in: | Toxicological sciences 2007-06, Vol.97 (2), p.533-538 |
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| creator | Okumura, Hirotoshi Katoh, Miki Sawada, Toshiro Nakajima, Miki Soeno, Yoshinori Yabuuchi, Hikaru Ikeda, Toshihiko Tateno, Chise Yoshizato, Katsutoshi Yokoi, Tsuyoshi |
| description | The liver of a chimeric urokinase-type plasminogen activator (uPA)+/+/severe combined immunodeficient (SCID) mouse line recently established in Japan could be replaced by more than 80% with human hepatocytes. We previously reported that the chimeric mice with humanized liver could be useful as a human model in studies on drug metabolism and pharmacokinetics. In the present study, the humanization of an excretory pathway was investigated in the chimeric mice. Cefmetazole (CMZ) was used as a probe drug. The CMZ excretions in urine and feces were 81.0 and 5.9% of the dose, respectively, in chimeric mice and were 23.7 and 59.4% of the dose, respectively, in control uPA−/−/SCID mice. Because CMZ is mainly excreted in urine in humans, the excretory profile of chimeric mice was demonstrated to be similar to that of humans. In the chimeric mice, the hepatic mRNA expression of human drug transporters could be quantified. On the other hand, the hepatic mRNA expression of mouse drug transporters in the chimeric mice was significantly lower than in the control uPA−/−/SCID mice. In conclusion, chimeric mice exhibited a humanized profile of drug excretion, suggesting that this chimeric mouse line would be a useful animal model in excretory studies. |
| doi_str_mv | 10.1093/toxsci/kfm041 |
| format | Article |
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We previously reported that the chimeric mice with humanized liver could be useful as a human model in studies on drug metabolism and pharmacokinetics. In the present study, the humanization of an excretory pathway was investigated in the chimeric mice. Cefmetazole (CMZ) was used as a probe drug. The CMZ excretions in urine and feces were 81.0 and 5.9% of the dose, respectively, in chimeric mice and were 23.7 and 59.4% of the dose, respectively, in control uPA−/−/SCID mice. Because CMZ is mainly excreted in urine in humans, the excretory profile of chimeric mice was demonstrated to be similar to that of humans. In the chimeric mice, the hepatic mRNA expression of human drug transporters could be quantified. On the other hand, the hepatic mRNA expression of mouse drug transporters in the chimeric mice was significantly lower than in the control uPA−/−/SCID mice. In conclusion, chimeric mice exhibited a humanized profile of drug excretion, suggesting that this chimeric mouse line would be a useful animal model in excretory studies.</description><identifier>ISSN: 1096-6080</identifier><identifier>EISSN: 1096-0929</identifier><identifier>DOI: 10.1093/toxsci/kfm041</identifier><identifier>PMID: 17341479</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Animals ; Anti-Bacterial Agents - pharmacokinetics ; Anti-Bacterial Agents - toxicity ; ATP-Binding Cassette Transporters - genetics ; ATP-Binding Cassette Transporters - metabolism ; biliary excretion ; Cefmetazole - pharmacokinetics ; Cefmetazole - toxicity ; Chemical and Drug Induced Liver Injury - genetics ; Chemical and Drug Induced Liver Injury - pathology ; CMZ ; Feces - chemistry ; Hepatocytes - physiology ; Humans ; Liver - cytology ; Liver - physiology ; Mice ; Mice, Inbred ICR ; Mice, SCID ; Mice, Transgenic - physiology ; Pharmaceutical Preparations - metabolism ; renal excretion ; RNA, Messenger - biosynthesis ; RNA, Messenger - genetics ; transporter ; Urokinase-Type Plasminogen Activator - genetics</subject><ispartof>Toxicological sciences, 2007-06, Vol.97 (2), p.533-538</ispartof><rights>The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c432t-a74c5e949e86e87188467201be98cdd7bbf67d90f1009f5e3b64a82d3ef3d4613</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,1585,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17341479$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Okumura, Hirotoshi</creatorcontrib><creatorcontrib>Katoh, Miki</creatorcontrib><creatorcontrib>Sawada, Toshiro</creatorcontrib><creatorcontrib>Nakajima, Miki</creatorcontrib><creatorcontrib>Soeno, Yoshinori</creatorcontrib><creatorcontrib>Yabuuchi, Hikaru</creatorcontrib><creatorcontrib>Ikeda, Toshihiko</creatorcontrib><creatorcontrib>Tateno, Chise</creatorcontrib><creatorcontrib>Yoshizato, Katsutoshi</creatorcontrib><creatorcontrib>Yokoi, Tsuyoshi</creatorcontrib><title>Humanization of Excretory Pathway in Chimeric Mice with Humanized Liver</title><title>Toxicological sciences</title><addtitle>Toxicol Sci</addtitle><description>The liver of a chimeric urokinase-type plasminogen activator (uPA)+/+/severe combined immunodeficient (SCID) mouse line recently established in Japan could be replaced by more than 80% with human hepatocytes. We previously reported that the chimeric mice with humanized liver could be useful as a human model in studies on drug metabolism and pharmacokinetics. In the present study, the humanization of an excretory pathway was investigated in the chimeric mice. Cefmetazole (CMZ) was used as a probe drug. The CMZ excretions in urine and feces were 81.0 and 5.9% of the dose, respectively, in chimeric mice and were 23.7 and 59.4% of the dose, respectively, in control uPA−/−/SCID mice. Because CMZ is mainly excreted in urine in humans, the excretory profile of chimeric mice was demonstrated to be similar to that of humans. In the chimeric mice, the hepatic mRNA expression of human drug transporters could be quantified. On the other hand, the hepatic mRNA expression of mouse drug transporters in the chimeric mice was significantly lower than in the control uPA−/−/SCID mice. In conclusion, chimeric mice exhibited a humanized profile of drug excretion, suggesting that this chimeric mouse line would be a useful animal model in excretory studies.</description><subject>Animals</subject><subject>Anti-Bacterial Agents - pharmacokinetics</subject><subject>Anti-Bacterial Agents - toxicity</subject><subject>ATP-Binding Cassette Transporters - genetics</subject><subject>ATP-Binding Cassette Transporters - metabolism</subject><subject>biliary excretion</subject><subject>Cefmetazole - pharmacokinetics</subject><subject>Cefmetazole - toxicity</subject><subject>Chemical and Drug Induced Liver Injury - genetics</subject><subject>Chemical and Drug Induced Liver Injury - pathology</subject><subject>CMZ</subject><subject>Feces - chemistry</subject><subject>Hepatocytes - physiology</subject><subject>Humans</subject><subject>Liver - cytology</subject><subject>Liver - physiology</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Mice, SCID</subject><subject>Mice, Transgenic - physiology</subject><subject>Pharmaceutical Preparations - metabolism</subject><subject>renal excretion</subject><subject>RNA, Messenger - biosynthesis</subject><subject>RNA, Messenger - genetics</subject><subject>transporter</subject><subject>Urokinase-Type Plasminogen Activator - genetics</subject><issn>1096-6080</issn><issn>1096-0929</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM9LwzAUx4MoTqdHr5KTeKkmTZY0RxlzEyY6_IF4CWn6yuLWdSat2_zr3WjRo6f3eHy-3wcfhM4ouaJEseuqXAfrrmd5QTjdQ0fbo4iIitV-uwuSkA46DuGDEEoFUYeoQyXjlEt1hIajujAL920qVy5wmePB2nqoSr_Bj6aarswGuwXuT10B3ll87yzglaumuM1BhsfuC_wJOsjNPMBpO7vo5Xbw3B9F44fhXf9mHFnO4ioyktseKK4gEZBImiRcyJjQFFRis0ymaS5kpkhOCVF5D1gquEnijEHOMi4o66KLpnfpy88aQqULFyzM52YBZR00VULKmO_AqAGtL0PwkOuld4XxG02J3pnTjTndmNvy521xnRaQ_dGtqi1w2QBlvfy3q_3tQgXrX9j4mRaSyZ4evb1r8TgeTtjkVT-xHyuNiOI</recordid><startdate>20070601</startdate><enddate>20070601</enddate><creator>Okumura, Hirotoshi</creator><creator>Katoh, Miki</creator><creator>Sawada, Toshiro</creator><creator>Nakajima, Miki</creator><creator>Soeno, Yoshinori</creator><creator>Yabuuchi, Hikaru</creator><creator>Ikeda, Toshihiko</creator><creator>Tateno, Chise</creator><creator>Yoshizato, Katsutoshi</creator><creator>Yokoi, Tsuyoshi</creator><general>Oxford University Press</general><scope>BSCLL</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>20070601</creationdate><title>Humanization of Excretory Pathway in Chimeric Mice with Humanized Liver</title><author>Okumura, Hirotoshi ; Katoh, Miki ; Sawada, Toshiro ; Nakajima, Miki ; Soeno, Yoshinori ; Yabuuchi, Hikaru ; Ikeda, Toshihiko ; Tateno, Chise ; Yoshizato, Katsutoshi ; Yokoi, Tsuyoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c432t-a74c5e949e86e87188467201be98cdd7bbf67d90f1009f5e3b64a82d3ef3d4613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Anti-Bacterial Agents - pharmacokinetics</topic><topic>Anti-Bacterial Agents - toxicity</topic><topic>ATP-Binding Cassette Transporters - genetics</topic><topic>ATP-Binding Cassette Transporters - metabolism</topic><topic>biliary excretion</topic><topic>Cefmetazole - pharmacokinetics</topic><topic>Cefmetazole - toxicity</topic><topic>Chemical and Drug Induced Liver Injury - genetics</topic><topic>Chemical and Drug Induced Liver Injury - pathology</topic><topic>CMZ</topic><topic>Feces - chemistry</topic><topic>Hepatocytes - physiology</topic><topic>Humans</topic><topic>Liver - cytology</topic><topic>Liver - physiology</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Mice, SCID</topic><topic>Mice, Transgenic - physiology</topic><topic>Pharmaceutical Preparations - metabolism</topic><topic>renal excretion</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - genetics</topic><topic>transporter</topic><topic>Urokinase-Type Plasminogen Activator - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Okumura, Hirotoshi</creatorcontrib><creatorcontrib>Katoh, Miki</creatorcontrib><creatorcontrib>Sawada, Toshiro</creatorcontrib><creatorcontrib>Nakajima, Miki</creatorcontrib><creatorcontrib>Soeno, Yoshinori</creatorcontrib><creatorcontrib>Yabuuchi, Hikaru</creatorcontrib><creatorcontrib>Ikeda, Toshihiko</creatorcontrib><creatorcontrib>Tateno, Chise</creatorcontrib><creatorcontrib>Yoshizato, Katsutoshi</creatorcontrib><creatorcontrib>Yokoi, Tsuyoshi</creatorcontrib><collection>Istex</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>Toxicological sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Okumura, Hirotoshi</au><au>Katoh, Miki</au><au>Sawada, Toshiro</au><au>Nakajima, Miki</au><au>Soeno, Yoshinori</au><au>Yabuuchi, Hikaru</au><au>Ikeda, Toshihiko</au><au>Tateno, Chise</au><au>Yoshizato, Katsutoshi</au><au>Yokoi, Tsuyoshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Humanization of Excretory Pathway in Chimeric Mice with Humanized Liver</atitle><jtitle>Toxicological sciences</jtitle><addtitle>Toxicol Sci</addtitle><date>2007-06-01</date><risdate>2007</risdate><volume>97</volume><issue>2</issue><spage>533</spage><epage>538</epage><pages>533-538</pages><issn>1096-6080</issn><eissn>1096-0929</eissn><abstract>The liver of a chimeric urokinase-type plasminogen activator (uPA)+/+/severe combined immunodeficient (SCID) mouse line recently established in Japan could be replaced by more than 80% with human hepatocytes. We previously reported that the chimeric mice with humanized liver could be useful as a human model in studies on drug metabolism and pharmacokinetics. In the present study, the humanization of an excretory pathway was investigated in the chimeric mice. Cefmetazole (CMZ) was used as a probe drug. The CMZ excretions in urine and feces were 81.0 and 5.9% of the dose, respectively, in chimeric mice and were 23.7 and 59.4% of the dose, respectively, in control uPA−/−/SCID mice. Because CMZ is mainly excreted in urine in humans, the excretory profile of chimeric mice was demonstrated to be similar to that of humans. In the chimeric mice, the hepatic mRNA expression of human drug transporters could be quantified. On the other hand, the hepatic mRNA expression of mouse drug transporters in the chimeric mice was significantly lower than in the control uPA−/−/SCID mice. In conclusion, chimeric mice exhibited a humanized profile of drug excretion, suggesting that this chimeric mouse line would be a useful animal model in excretory studies.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>17341479</pmid><doi>10.1093/toxsci/kfm041</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Animals Anti-Bacterial Agents - pharmacokinetics Anti-Bacterial Agents - toxicity ATP-Binding Cassette Transporters - genetics ATP-Binding Cassette Transporters - metabolism biliary excretion Cefmetazole - pharmacokinetics Cefmetazole - toxicity Chemical and Drug Induced Liver Injury - genetics Chemical and Drug Induced Liver Injury - pathology CMZ Feces - chemistry Hepatocytes - physiology Humans Liver - cytology Liver - physiology Mice Mice, Inbred ICR Mice, SCID Mice, Transgenic - physiology Pharmaceutical Preparations - metabolism renal excretion RNA, Messenger - biosynthesis RNA, Messenger - genetics transporter Urokinase-Type Plasminogen Activator - genetics |
| title | Humanization of Excretory Pathway in Chimeric Mice with Humanized Liver |
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