Effect of Nuclear Receptor Downregulation on Hepatic Expression of Cytochrome P450 and Transporters in Chronic Hepatitis C in Association with Fibrosis Development
Analysis of mRNAs from liver biopsy samples of patients with chronic hepatitis C revealed that the levels of nuclear receptor expression were correlated with those of drug-metabolizing enzymes and transporters in relation to the development of fibrosis. Overall, the median mRNA level was largely dep...
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| Veröffentlicht in: | Drug metabolism and pharmacokinetics 2012, Vol.27 (3), p.301-306 |
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| creator | Hanada, Kazuhiko Nakai, Kenya Tanaka, Hiromasa Suzuki, Fumitaka Kumada, Hiromitsu Ohno, Yasuo Ozawa, Shogo Ogata, Hiroyasu |
| description | Analysis of mRNAs from liver biopsy samples of patients with chronic hepatitis C revealed that the levels of nuclear receptor expression were correlated with those of drug-metabolizing enzymes and transporters in relation to the development of fibrosis. Overall, the median mRNA level was largely dependent on fibrosis stage (F), and that for stage 3 patients (F3) was about 50% less than that for F1 patients. Levels of expression of AhR, together with CAR and PXR, were lowest in livers of F3 patients. Multivariate linear regression analysis revealed that AhR expression appeared to be involved in the regulation of CYP1A2, 2E1, 2D6, UGT1A, MDR1/3, MRP2/3, NTCP and OCT1 in the livers of patients with chronic hepatitis C. These results suggest that downregulation of AhR during the progression of liver fibrosis is associated with decreased expression levels of these phase I and II enzymes and drug transporters during inflammation-related signal transduction between AhR and other nuclear receptors. |
| doi_str_mv | 10.2133/dmpk.DMPK-11-RG-077 |
| format | Article |
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Overall, the median mRNA level was largely dependent on fibrosis stage (F), and that for stage 3 patients (F3) was about 50% less than that for F1 patients. Levels of expression of AhR, together with CAR and PXR, were lowest in livers of F3 patients. Multivariate linear regression analysis revealed that AhR expression appeared to be involved in the regulation of CYP1A2, 2E1, 2D6, UGT1A, MDR1/3, MRP2/3, NTCP and OCT1 in the livers of patients with chronic hepatitis C. 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These results suggest that downregulation of AhR during the progression of liver fibrosis is associated with decreased expression levels of these phase I and II enzymes and drug transporters during inflammation-related signal transduction between AhR and other nuclear receptors.</description><subject>Adult</subject><subject>ATP Binding Cassette Transporter, Sub-Family B - genetics</subject><subject>ATP Binding Cassette Transporter, Sub-Family B - metabolism</subject><subject>Basic Helix-Loop-Helix Transcription Factors - genetics</subject><subject>Basic Helix-Loop-Helix Transcription Factors - metabolism</subject><subject>Biopsy</subject><subject>Cell Nucleus - metabolism</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>cytochrome P450 and transporters</subject><subject>Disease Progression</subject><subject>Down-Regulation</subject><subject>Female</subject><subject>Fibrosis</subject><subject>Gene Expression Regulation</subject><subject>Glucuronosyltransferase - genetics</subject><subject>Glucuronosyltransferase - metabolism</subject><subject>hepatitis C</subject><subject>Hepatitis C, Chronic - enzymology</subject><subject>Hepatitis C, Chronic - immunology</subject><subject>Hepatitis C, Chronic - metabolism</subject><subject>Hepatitis C, Chronic - pathology</subject><subject>Humans</subject><subject>Liver - immunology</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>liver fibrosis</subject><subject>Male</subject><subject>Middle Aged</subject><subject>mRNA downregulation</subject><subject>nuclear receptors</subject><subject>Organic Anion Transporters, Sodium-Dependent - genetics</subject><subject>Organic Anion Transporters, Sodium-Dependent - metabolism</subject><subject>Organic Cation Transporter 1 - genetics</subject><subject>Organic Cation Transporter 1 - metabolism</subject><subject>Receptors, Aryl Hydrocarbon - genetics</subject><subject>Receptors, Aryl Hydrocarbon - metabolism</subject><subject>Receptors, Cytoplasmic and Nuclear - genetics</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Receptors, Steroid - genetics</subject><subject>Receptors, Steroid - metabolism</subject><subject>RNA, Messenger - metabolism</subject><subject>Symporters - genetics</subject><subject>Symporters - metabolism</subject><issn>1347-4367</issn><issn>1880-0920</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1v1DAQjSpQW0p_ARLykUuKv_J14FBlt1tEgWrVni2vM6GGxE5tp6W_hz_KLCkckSx59Oa9N_a8LHvD6BlnQrzvxunH2erz9aecsXy7yWlVHWTHrK5pThtOX2AtZJVLUVZH2asYv1MqRCH5YXbEOSvLuqHH2a9134NJxPfky2wG0IFswcCUfCAr_-gCfJsHnax3BM8lTFgbsv45BYjxD9qT9il5cxf8CORaFpRo15GboF2cfEgQIrGOtNh3qFwcko2k3cPnMXpjF_9Hm-7Ihd0FH7G9ggcY_DSCS6-zl70eIpw-3yfZ7cX6pr3Mr75uPrbnV7mRTZNyTqWuodG6r3Z1rSVHtKRNRXElTFLogHGqRVHTrqwFY2JXACuobnrGmcSNnmTvFt8p-PsZYlKjjQaGQTvwc1SMoqUoi4YhVSxUg6-NAXo1BTvq8IQktU9H7dNR-3QUY2q7UZgOqt4-D5h3I3T_NH_jQMKHhQD4zQcLQUVjwRnobMCUVOftfwf8BjQCozk</recordid><startdate>2012</startdate><enddate>2012</enddate><creator>Hanada, Kazuhiko</creator><creator>Nakai, Kenya</creator><creator>Tanaka, Hiromasa</creator><creator>Suzuki, Fumitaka</creator><creator>Kumada, Hiromitsu</creator><creator>Ohno, Yasuo</creator><creator>Ozawa, Shogo</creator><creator>Ogata, Hiroyasu</creator><general>Elsevier Ltd</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></search><sort><creationdate>2012</creationdate><title>Effect of Nuclear Receptor Downregulation on Hepatic Expression of Cytochrome P450 and Transporters in Chronic Hepatitis C in Association with Fibrosis Development</title><author>Hanada, Kazuhiko ; Nakai, Kenya ; Tanaka, Hiromasa ; Suzuki, Fumitaka ; Kumada, Hiromitsu ; Ohno, Yasuo ; Ozawa, Shogo ; Ogata, Hiroyasu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-204a8e9aaf7b88a4249960970188140ede120a3580d683113b5e150a9f1214133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>ATP Binding Cassette Transporter, Sub-Family B - genetics</topic><topic>ATP Binding Cassette Transporter, Sub-Family B - metabolism</topic><topic>Basic Helix-Loop-Helix Transcription Factors - genetics</topic><topic>Basic Helix-Loop-Helix Transcription Factors - metabolism</topic><topic>Biopsy</topic><topic>Cell Nucleus - metabolism</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>cytochrome P450 and transporters</topic><topic>Disease Progression</topic><topic>Down-Regulation</topic><topic>Female</topic><topic>Fibrosis</topic><topic>Gene Expression Regulation</topic><topic>Glucuronosyltransferase - genetics</topic><topic>Glucuronosyltransferase - metabolism</topic><topic>hepatitis C</topic><topic>Hepatitis C, Chronic - enzymology</topic><topic>Hepatitis C, Chronic - immunology</topic><topic>Hepatitis C, Chronic - metabolism</topic><topic>Hepatitis C, Chronic - pathology</topic><topic>Humans</topic><topic>Liver - immunology</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>liver fibrosis</topic><topic>Male</topic><topic>Middle Aged</topic><topic>mRNA downregulation</topic><topic>nuclear receptors</topic><topic>Organic Anion Transporters, Sodium-Dependent - genetics</topic><topic>Organic Anion Transporters, Sodium-Dependent - metabolism</topic><topic>Organic Cation Transporter 1 - genetics</topic><topic>Organic Cation Transporter 1 - metabolism</topic><topic>Receptors, Aryl Hydrocarbon - genetics</topic><topic>Receptors, Aryl Hydrocarbon - metabolism</topic><topic>Receptors, Cytoplasmic and Nuclear - genetics</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Receptors, Steroid - genetics</topic><topic>Receptors, Steroid - metabolism</topic><topic>RNA, Messenger - metabolism</topic><topic>Symporters - genetics</topic><topic>Symporters - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hanada, Kazuhiko</creatorcontrib><creatorcontrib>Nakai, Kenya</creatorcontrib><creatorcontrib>Tanaka, Hiromasa</creatorcontrib><creatorcontrib>Suzuki, Fumitaka</creatorcontrib><creatorcontrib>Kumada, Hiromitsu</creatorcontrib><creatorcontrib>Ohno, Yasuo</creatorcontrib><creatorcontrib>Ozawa, Shogo</creatorcontrib><creatorcontrib>Ogata, Hiroyasu</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><jtitle>Drug metabolism and pharmacokinetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hanada, Kazuhiko</au><au>Nakai, Kenya</au><au>Tanaka, Hiromasa</au><au>Suzuki, Fumitaka</au><au>Kumada, Hiromitsu</au><au>Ohno, Yasuo</au><au>Ozawa, Shogo</au><au>Ogata, Hiroyasu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of Nuclear Receptor Downregulation on Hepatic Expression of Cytochrome P450 and Transporters in Chronic Hepatitis C in Association with Fibrosis Development</atitle><jtitle>Drug metabolism and pharmacokinetics</jtitle><addtitle>Drug Metab Pharmacokinet</addtitle><date>2012</date><risdate>2012</risdate><volume>27</volume><issue>3</issue><spage>301</spage><epage>306</epage><pages>301-306</pages><issn>1347-4367</issn><eissn>1880-0920</eissn><abstract>Analysis of mRNAs from liver biopsy samples of patients with chronic hepatitis C revealed that the levels of nuclear receptor expression were correlated with those of drug-metabolizing enzymes and transporters in relation to the development of fibrosis. Overall, the median mRNA level was largely dependent on fibrosis stage (F), and that for stage 3 patients (F3) was about 50% less than that for F1 patients. Levels of expression of AhR, together with CAR and PXR, were lowest in livers of F3 patients. Multivariate linear regression analysis revealed that AhR expression appeared to be involved in the regulation of CYP1A2, 2E1, 2D6, UGT1A, MDR1/3, MRP2/3, NTCP and OCT1 in the livers of patients with chronic hepatitis C. These results suggest that downregulation of AhR during the progression of liver fibrosis is associated with decreased expression levels of these phase I and II enzymes and drug transporters during inflammation-related signal transduction between AhR and other nuclear receptors.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>22166890</pmid><doi>10.2133/dmpk.DMPK-11-RG-077</doi><tpages>6</tpages></addata></record> |
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| ispartof | Drug metabolism and pharmacokinetics, 2012, Vol.27 (3), p.301-306 |
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| subjects | Adult ATP Binding Cassette Transporter, Sub-Family B - genetics ATP Binding Cassette Transporter, Sub-Family B - metabolism Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - metabolism Biopsy Cell Nucleus - metabolism Cytochrome P-450 Enzyme System - genetics Cytochrome P-450 Enzyme System - metabolism cytochrome P450 and transporters Disease Progression Down-Regulation Female Fibrosis Gene Expression Regulation Glucuronosyltransferase - genetics Glucuronosyltransferase - metabolism hepatitis C Hepatitis C, Chronic - enzymology Hepatitis C, Chronic - immunology Hepatitis C, Chronic - metabolism Hepatitis C, Chronic - pathology Humans Liver - immunology Liver - metabolism Liver - pathology liver fibrosis Male Middle Aged mRNA downregulation nuclear receptors Organic Anion Transporters, Sodium-Dependent - genetics Organic Anion Transporters, Sodium-Dependent - metabolism Organic Cation Transporter 1 - genetics Organic Cation Transporter 1 - metabolism Receptors, Aryl Hydrocarbon - genetics Receptors, Aryl Hydrocarbon - metabolism Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - metabolism Receptors, Steroid - genetics Receptors, Steroid - metabolism RNA, Messenger - metabolism Symporters - genetics Symporters - metabolism |
| title | Effect of Nuclear Receptor Downregulation on Hepatic Expression of Cytochrome P450 and Transporters in Chronic Hepatitis C in Association with Fibrosis Development |
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