Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro
Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Cognex®), a simple acridine, is a reversible inhibitor of cholinesterase activity available for the symptomatic treatment of Alzheimer’s disease. Tacrin...
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| Veröffentlicht in: | Journal of applied toxicology 1999-01, Vol.19 (1), p.31-38 |
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| description | Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Cognex®), a simple acridine, is a reversible inhibitor of cholinesterase activity available for the symptomatic treatment of Alzheimer’s disease. Tacrine therapy causes sporadic elevations of aminotransferases in humans, and tacrine alters protein synthesis and ribosomal structure under short‐term in vitro exposures in isolated hepatocytes from humans and other species. There is no clear relationship between transaminase elevation and liver damage in humans, and prolonged drug exposure to animals does not result in hepatic insult. Subcellular alterations have been described in isolated human and rodent hepatocytes, including degranulation and vesiculation of the endoplasmic reticulum (ER), aggregation of electron‐dense structures within the ER, altered nuclei and nucleoli and detrimental structural and functional effects to mitochondria. Whether these changes in hepatocyte morphology and function are unique to tacrine or not is unknown, as human hepatocytes exposed to more complex acridines have not been characterized. In this study, we extended the results of in vitro studies with tacrine to acridine orange, 9‐aminoacridine, quinacrine and proflavin. In primary human hepatocytes, these compounds caused a similar reduction of mitochondrial membrane potential with parallel ultrastructural changes. The 1‐hydroxy and 7‐hydroxy tacrine metabolites, acridine hydrochloride and acridine 9‐carboxylic acid, and the non‐acridine cholinesterase inhibitor eserine, did not induce characteristic subcellular ER changes but damaged mitochondria structure, reduced mitochondrial membrane potential and were cytotoxic. These data indicate that the tacrine‐like subcellular changes in hepatocytes are reproducible with other acridines and cause mitochondrial dysfunction in human hepatocytes. Copyright © 1998 John Wiley & Sons, Ltd. |
| doi_str_mv | 10.1002/(SICI)1099-1263(199901/02)19:1<31::AID-JAT535>3.0.CO;2-6 |
| format | Article |
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De La</creator><creatorcontrib>Plymale, Douglas R. ; Iglesia, Felix A. De La</creatorcontrib><description>Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Cognex®), a simple acridine, is a reversible inhibitor of cholinesterase activity available for the symptomatic treatment of Alzheimer’s disease. Tacrine therapy causes sporadic elevations of aminotransferases in humans, and tacrine alters protein synthesis and ribosomal structure under short‐term in vitro exposures in isolated hepatocytes from humans and other species. There is no clear relationship between transaminase elevation and liver damage in humans, and prolonged drug exposure to animals does not result in hepatic insult. Subcellular alterations have been described in isolated human and rodent hepatocytes, including degranulation and vesiculation of the endoplasmic reticulum (ER), aggregation of electron‐dense structures within the ER, altered nuclei and nucleoli and detrimental structural and functional effects to mitochondria. Whether these changes in hepatocyte morphology and function are unique to tacrine or not is unknown, as human hepatocytes exposed to more complex acridines have not been characterized. In this study, we extended the results of in vitro studies with tacrine to acridine orange, 9‐aminoacridine, quinacrine and proflavin. In primary human hepatocytes, these compounds caused a similar reduction of mitochondrial membrane potential with parallel ultrastructural changes. The 1‐hydroxy and 7‐hydroxy tacrine metabolites, acridine hydrochloride and acridine 9‐carboxylic acid, and the non‐acridine cholinesterase inhibitor eserine, did not induce characteristic subcellular ER changes but damaged mitochondria structure, reduced mitochondrial membrane potential and were cytotoxic. These data indicate that the tacrine‐like subcellular changes in hepatocytes are reproducible with other acridines and cause mitochondrial dysfunction in human hepatocytes. Copyright © 1998 John Wiley & Sons, Ltd.</description><identifier>ISSN: 0260-437X</identifier><identifier>EISSN: 1099-1263</identifier><identifier>DOI: 10.1002/(SICI)1099-1263(199901/02)19:1<31::AID-JAT535>3.0.CO;2-6</identifier><identifier>PMID: 9989475</identifier><identifier>CODEN: JJATDK</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>acridines ; Acridines - toxicity ; Biological and medical sciences ; Cells, Cultured ; Chemical and industrial products toxicology. Toxic occupational diseases ; cognex ; cytotoxicity ; Drug toxicity and drugs side effects treatment ; electron microscopy ; Endoplasmic Reticulum - drug effects ; Fluorescence ; Humans ; Intracellular Membranes - drug effects ; Liver - drug effects ; Liver - ultrastructure ; Medical sciences ; Membrane Potentials - drug effects ; Microscopy, Electron ; mitochondria ; Mitochondria, Liver - drug effects ; Permeability - drug effects ; Pharmacology. 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De La</creatorcontrib><title>Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro</title><title>Journal of applied toxicology</title><addtitle>J. Appl. Toxicol</addtitle><description>Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Cognex®), a simple acridine, is a reversible inhibitor of cholinesterase activity available for the symptomatic treatment of Alzheimer’s disease. Tacrine therapy causes sporadic elevations of aminotransferases in humans, and tacrine alters protein synthesis and ribosomal structure under short‐term in vitro exposures in isolated hepatocytes from humans and other species. There is no clear relationship between transaminase elevation and liver damage in humans, and prolonged drug exposure to animals does not result in hepatic insult. Subcellular alterations have been described in isolated human and rodent hepatocytes, including degranulation and vesiculation of the endoplasmic reticulum (ER), aggregation of electron‐dense structures within the ER, altered nuclei and nucleoli and detrimental structural and functional effects to mitochondria. Whether these changes in hepatocyte morphology and function are unique to tacrine or not is unknown, as human hepatocytes exposed to more complex acridines have not been characterized. In this study, we extended the results of in vitro studies with tacrine to acridine orange, 9‐aminoacridine, quinacrine and proflavin. In primary human hepatocytes, these compounds caused a similar reduction of mitochondrial membrane potential with parallel ultrastructural changes. The 1‐hydroxy and 7‐hydroxy tacrine metabolites, acridine hydrochloride and acridine 9‐carboxylic acid, and the non‐acridine cholinesterase inhibitor eserine, did not induce characteristic subcellular ER changes but damaged mitochondria structure, reduced mitochondrial membrane potential and were cytotoxic. These data indicate that the tacrine‐like subcellular changes in hepatocytes are reproducible with other acridines and cause mitochondrial dysfunction in human hepatocytes. Copyright © 1998 John Wiley & Sons, Ltd.</description><subject>acridines</subject><subject>Acridines - toxicity</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Chemical and industrial products toxicology. Toxic occupational diseases</subject><subject>cognex</subject><subject>cytotoxicity</subject><subject>Drug toxicity and drugs side effects treatment</subject><subject>electron microscopy</subject><subject>Endoplasmic Reticulum - drug effects</subject><subject>Fluorescence</subject><subject>Humans</subject><subject>Intracellular Membranes - drug effects</subject><subject>Liver - drug effects</subject><subject>Liver - ultrastructure</subject><subject>Medical sciences</subject><subject>Membrane Potentials - drug effects</subject><subject>Microscopy, Electron</subject><subject>mitochondria</subject><subject>Mitochondria, Liver - drug effects</subject><subject>Permeability - drug effects</subject><subject>Pharmacology. Drug treatments</subject><subject>tacrine</subject><subject>Toxicity: digestive system</subject><subject>Toxicology</subject><subject>Various organic compounds</subject><issn>0260-437X</issn><issn>1099-1263</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkV1v0zAUhi0EGt3gJyDlAqHtIp0_aicuE1oV2ChUFInBpt0cOY5DPVKnxAms_x5HiYpkydJ5P47sB6FLgqcEY3p--m2ZLc8IljImVLBTIqXE5BzTMyLn5IKR-XyxfB9_Wtxwxt-xKZ5m67c0Fk_Q5BB6iiaYChzPWHL3HB17_4Bx0Gh6hI6kTOUs4RN0v9CNLawzsXVFp00R-S7Xpqq6SjWRckVUdk63tnaqivRGuZ_GR9ZF1teVaoN9022VizZmp9pa79tB_WPbpn6BnpWq8ubleJ-g71cfbrKP8Wp9vcwWq9iyNOFxUXIjGZ0xEfYSknIsEkO4krnkRZEXvCzThJY4wSkuS5YrQ1kuKQ9hEmKanaA3Q--uqX93xrewtb5_gnKm7jyQhIbaGQvGV6Oxy7emgF1jt6rZw_gZQX896sprVZWNctr6g40IKcIJtvvB9tdWZv9fxtCjg54c9BCghwADOQgCCRNgBAI4GMABAwzZGiiIcRLK46Hc-tY8HspV8wtEwhIOt1-u4asQq893P26Bsn-WY6Da</recordid><startdate>199901</startdate><enddate>199901</enddate><creator>Plymale, Douglas R.</creator><creator>Iglesia, Felix A. De La</creator><general>John Wiley & Sons, Ltd</general><general>Wiley</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>199901</creationdate><title>Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro</title><author>Plymale, Douglas R. ; Iglesia, Felix A. De La</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-i3875-df5e932436bce1185067e15a9b95ddbd5ff872f07080ff3bae23b9253871324c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>acridines</topic><topic>Acridines - toxicity</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Chemical and industrial products toxicology. Toxic occupational diseases</topic><topic>cognex</topic><topic>cytotoxicity</topic><topic>Drug toxicity and drugs side effects treatment</topic><topic>electron microscopy</topic><topic>Endoplasmic Reticulum - drug effects</topic><topic>Fluorescence</topic><topic>Humans</topic><topic>Intracellular Membranes - drug effects</topic><topic>Liver - drug effects</topic><topic>Liver - ultrastructure</topic><topic>Medical sciences</topic><topic>Membrane Potentials - drug effects</topic><topic>Microscopy, Electron</topic><topic>mitochondria</topic><topic>Mitochondria, Liver - drug effects</topic><topic>Permeability - drug effects</topic><topic>Pharmacology. Drug treatments</topic><topic>tacrine</topic><topic>Toxicity: digestive system</topic><topic>Toxicology</topic><topic>Various organic compounds</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Plymale, Douglas R.</creatorcontrib><creatorcontrib>Iglesia, Felix A. De La</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Journal of applied toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Plymale, Douglas R.</au><au>Iglesia, Felix A. De La</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro</atitle><jtitle>Journal of applied toxicology</jtitle><addtitle>J. Appl. Toxicol</addtitle><date>1999-01</date><risdate>1999</risdate><volume>19</volume><issue>1</issue><spage>31</spage><epage>38</epage><pages>31-38</pages><issn>0260-437X</issn><eissn>1099-1263</eissn><coden>JJATDK</coden><abstract>Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Cognex®), a simple acridine, is a reversible inhibitor of cholinesterase activity available for the symptomatic treatment of Alzheimer’s disease. Tacrine therapy causes sporadic elevations of aminotransferases in humans, and tacrine alters protein synthesis and ribosomal structure under short‐term in vitro exposures in isolated hepatocytes from humans and other species. There is no clear relationship between transaminase elevation and liver damage in humans, and prolonged drug exposure to animals does not result in hepatic insult. Subcellular alterations have been described in isolated human and rodent hepatocytes, including degranulation and vesiculation of the endoplasmic reticulum (ER), aggregation of electron‐dense structures within the ER, altered nuclei and nucleoli and detrimental structural and functional effects to mitochondria. Whether these changes in hepatocyte morphology and function are unique to tacrine or not is unknown, as human hepatocytes exposed to more complex acridines have not been characterized. In this study, we extended the results of in vitro studies with tacrine to acridine orange, 9‐aminoacridine, quinacrine and proflavin. In primary human hepatocytes, these compounds caused a similar reduction of mitochondrial membrane potential with parallel ultrastructural changes. The 1‐hydroxy and 7‐hydroxy tacrine metabolites, acridine hydrochloride and acridine 9‐carboxylic acid, and the non‐acridine cholinesterase inhibitor eserine, did not induce characteristic subcellular ER changes but damaged mitochondria structure, reduced mitochondrial membrane potential and were cytotoxic. These data indicate that the tacrine‐like subcellular changes in hepatocytes are reproducible with other acridines and cause mitochondrial dysfunction in human hepatocytes. Copyright © 1998 John Wiley & Sons, Ltd.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>9989475</pmid><doi>10.1002/(SICI)1099-1263(199901/02)19:1<31::AID-JAT535>3.0.CO;2-6</doi><tpages>8</tpages></addata></record> |
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| ispartof | Journal of applied toxicology, 1999-01, Vol.19 (1), p.31-38 |
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| subjects | acridines Acridines - toxicity Biological and medical sciences Cells, Cultured Chemical and industrial products toxicology. Toxic occupational diseases cognex cytotoxicity Drug toxicity and drugs side effects treatment electron microscopy Endoplasmic Reticulum - drug effects Fluorescence Humans Intracellular Membranes - drug effects Liver - drug effects Liver - ultrastructure Medical sciences Membrane Potentials - drug effects Microscopy, Electron mitochondria Mitochondria, Liver - drug effects Permeability - drug effects Pharmacology. Drug treatments tacrine Toxicity: digestive system Toxicology Various organic compounds |
| title | Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro |
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